JPH01246287A - Novel camptothecin derivative and production thereof - Google Patents
Novel camptothecin derivative and production thereofInfo
- Publication number
- JPH01246287A JPH01246287A JP7342688A JP7342688A JPH01246287A JP H01246287 A JPH01246287 A JP H01246287A JP 7342688 A JP7342688 A JP 7342688A JP 7342688 A JP7342688 A JP 7342688A JP H01246287 A JPH01246287 A JP H01246287A
- Authority
- JP
- Japan
- Prior art keywords
- fatty acid
- formula
- camptothecin
- acyl group
- hydroxyl group
- 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.)
- Granted
Links
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 125000002252 acyl group Chemical group 0.000 claims abstract description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 13
- 229930195729 fatty acid Natural products 0.000 claims abstract description 13
- 239000000194 fatty acid Substances 0.000 claims abstract description 13
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940127093 camptothecin Drugs 0.000 claims abstract description 12
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 11
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims abstract 2
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims abstract 2
- -1 carbodiimide compound Chemical class 0.000 claims description 4
- 150000004671 saturated fatty acids Chemical class 0.000 claims description 4
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 3
- 239000012285 osmium tetroxide Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 238000003818 flash chromatography Methods 0.000 abstract description 6
- 150000002148 esters Chemical class 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 230000002829 reductive effect Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- IHUHXSNGMLUYES-UHFFFAOYSA-J osmium(iv) chloride Chemical compound Cl[Os](Cl)(Cl)Cl IHUHXSNGMLUYES-UHFFFAOYSA-J 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000007385 chemical modification Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 235000020138 yakult Nutrition 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は医薬もしくはその中間体として有用なカンプト
テシンの２０位水酸基における高級脂肪酸とのエステル
誘導体およびその製造法に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an ester derivative of camptothecin with a higher fatty acid at the 20-position hydroxyl group, which is useful as a drug or an intermediate thereof, and a method for producing the same.
カンプトテシンは、落葉喬木喜樹（ｃａｍｐｔｏｔｈｅ
ｃααｃｕｍｉｎａｔα）等から抽出、単離されるアル
カロイドで、強力な核酸合成阻害作用を有し、その作用
は迅速かつ可逆性を示すことが特徴であり、既存の抗ガ
ン剤と交叉耐性を示さないという独特な作用機作をもつ
抗腫瘍性の物質で、マウスＬ１２１０白血病、ラットの
ウォーカー２５６肉腫などの実験移植ガンに対し強力な
制ガン効果を示すことが認められているが、毒性作用を
有するために、医薬品としての有用性がおのずから制限
されているのが現状である。Camptothecin is derived from camptothecin.
An alkaloid extracted and isolated from plants such as cααcuminatα, it has a strong nucleic acid synthesis inhibitory effect, and its action is rapid and reversible.It is unique in that it does not show cross-resistance with existing anticancer drugs. It is an antitumor substance with a unique mechanism of action, and is recognized to have strong anticancer effects against experimentally transplanted cancers such as L1210 leukemia in mice and Walker 256 sarcoma in rats. Currently, their usefulness as pharmaceuticals is naturally limited.
そこでこのカンプトテシンをその誘導体に変えることに
よυ制ガン活性を保持しながら、毒性の低下を図る試み
が従来なされて米た。しかしながら、カンプトテシンの
各種有機溶剤に対する難溶性や、その構造中のへテロ環
に由来する親電子置換反応に対する抵抗性などの理由で
、誘導体に変換するにも、種々の障害があり、机上で企
画するほどに新規な誘導体を得ることは容易でないのが
実状である。Therefore, attempts have been made to reduce toxicity while retaining anticancer activity by changing camptothecin to its derivatives. However, due to the poor solubility of camptothecin in various organic solvents and the resistance to electrophilic substitution reactions derived from the heterocycle in its structure, there are various obstacles to converting it into derivatives, and it has not been possible to plan it on paper. The reality is that it is not easy to obtain novel derivatives.
カンプトテシンの２０位水酸基についての化−学的修飾
に関しては、単純なアシル（１（例えば、アセチル化、
ヘキサノイル化など）が知られている〔例えば、Ｊ、Ａ
ｙｎｅｒ、Ｃｈｅｍ、 Ｓｏｃ、、 ８８．３８８８（
１９６６）、Ｐｈｙｔｏｃｈｅｍｉｓｔｒｙ、 １８．
１０８５ （１９７９）参照〕。Regarding the chemical modification of the 20-hydroxyl group of camptothecin, simple acyl (1 (e.g., acetylation,
hexanoylation, etc.) [for example, J, A
yner, Chem, Soc,, 88.3888 (
1966), Phytochemistry, 18.
1085 (1979)].
このようにして得られた修飾体には、制ガン活性は見ら
れない。また、種々の立体障害を有するアシル基、もし
くは、官能基を有するアシル基は通常の反応操作では導
入することが困難であり、従来、この２０位水酸基の化
学的修飾による生理活性や物理的性質の改善の試みは行
うことができない状況にあった。The modified product thus obtained does not exhibit anticancer activity. In addition, it is difficult to introduce acyl groups with various steric hindrances or functional groups through normal reaction operations, and conventionally, chemical modification of the 20-position hydroxyl group has been used to improve physiological activity and physical properties. Attempts to improve the situation were not possible.
本発明者は、カンプトテシンの２０位における高級脂肪
酸エステルを合成することについて種々検討した結果、
カンプトテシンと高級脂肪酸とを適当な塩基物質の存在
下に、カルボジイミド型の縮合剤で処理することにより
高収率で目的とする２０位におけるエステルが得られる
ことを見出した。As a result of various studies on the synthesis of higher fatty acid esters at position 20 of camptothecin, the present inventor found that
It has been found that the desired ester at position 20 can be obtained in high yield by treating camptothecin and a higher fatty acid with a carbodiimide type condensing agent in the presence of an appropriate base substance.
すなわち、本発明は、新規化合物として、−数式（Ｉ）
（式中Ｒ１は炭素原子数１６〜２０の飽和もしくは不飽
和の高級脂肪酸のアシル基であシ、このアシル基は、置
換基として水酸基を有していてもよい）で表わされるカ
ンプトテシンの誘導体を提供するものであυ、また、そ
の製造法として、カンプトテシンと飽和もしくは不飽和
の高級脂肪酸とを塩基物質の存在下に、カルボジイミド
化合物を縮合剤として用いて処理してエステル化するこ
とを特徴とする一般式（ＩＩ）（式中、Ｒ２は飽和もし
くは不飽和の萬級脂肪酸のアシル基を示す）で表わされ
るカンプトテシン誘導体の製造法を提供するものである
。That is, the present invention provides a novel compound having the formula (I) (wherein R1 is an acyl group of a saturated or unsaturated higher fatty acid having 16 to 20 carbon atoms, and this acyl group has a hydroxyl group as a substituent. The present invention provides a derivative of camptothecin represented by A method for producing a camptothecin derivative represented by general formula (II) (wherein R2 represents an acyl group of a saturated or unsaturated 1000-grade fatty acid), which is characterized by esterification by treatment using a condensing agent. This is what we provide.
上記の製造法において用いられる塩基物質としては、特
定されないが、特に、４−Ｎ、Ｎ−ジメチルアミノピリ
ジンを用いるのが好ましＩ、１゜また、カルボジイミド
型化合物の縮合剤としてはエステル化に適する種々のタ
イプのものが知られているが、本発明の上記製造法にお
いても、特に特定はされないが、ジシクロへキシルカル
ボジイミドが、好ましく用いられる。The basic substance used in the above production method is not specified, but it is particularly preferable to use 4-N,N-dimethylaminopyridine. Although various suitable types are known, dicyclohexylcarbodiimide is preferably used in the above production method of the present invention, although it is not particularly specified.
また、本発明者らは、上記製造法により得られた不飽和
の扁級脂肪酸のエステルを四散イヒオスミウムで処理し
、そのアシル基中の不飽和結合に対し、水酸基を導入し
て、水酸基を有する飽和脂肪酸のアシル基とし得ること
を見出した。In addition, the present inventors treated the unsaturated flat fatty acid ester obtained by the above production method with tetradispersed ichiosmium, introduced a hydroxyl group into the unsaturated bond in the acyl group, and removed the hydroxyl group. It has been found that the acyl group of a saturated fatty acid can be used as the acyl group of a saturated fatty acid.
すなわち、本発明は、さらに、−数式（Ｉ［０（式中、
Ｒ３は不飽和脂肪酸のアシル基を示す）で表わされるカ
ンプトテシン誘導体を四酸化オスミウムで処理すること
を特徴とする一般式（財）（式中、Ｒ４は、置換基とし
て水酸基を有する飽和脂肪酸のアシル基を示す）で表わ
されるカンプトテシン誘導体の製造法を提供するもので
ある。That is, the present invention further provides - formula (I[0 (in the formula,
A camptothecin derivative represented by the general formula (In the formula, R4 represents an acyl group of a saturated fatty acid having a hydroxyl group as a substituent) is treated with osmium tetroxide. The present invention provides a method for producing a camptothecin derivative represented by the following formula.
通常、水酸基を有する脂肪酸のアシル基の導入には、そ
の水酸基に対する保護基の導入さらには、その保護基の
脱離という煩雑な工程を必要とするが、本発明に係る上
記の製造法によれば、簡便な操作をもって、高収率で目
的とする水酸基を有するアシル基を持つエステルを得る
ことができる。Normally, the introduction of an acyl group into a fatty acid having a hydroxyl group requires a complicated process of introducing a protective group to the hydroxyl group and removing the protective group. For example, the desired ester having an acyl group having a hydroxyl group can be obtained in high yield with a simple operation.
本発明に係る上記の方法によ軌アシル基中に、２重結合
を１個ないし３個有しているような脂肪酸とのエステル
誘導体についてその２重結合の個数に対応するモル数の
四酸化オスミウムを用いて反応させることによシ、対応
する２重結合の各位置に水酸基を導入することができる
。In the above-described method according to the present invention, tetroxidation of an ester derivative with a fatty acid having 1 to 3 double bonds in the acyl group is carried out in the number of moles corresponding to the number of double bonds. By reacting with osmium, a hydroxyl group can be introduced into each position of the corresponding double bond.
本発明に係る前記式（Ｉ）で表わされるカンプトテシン
誘導体は、制ガン活性を有しておシ、また、カンプトテ
シンの２０位の水酸基を効率的に化学的に修飾する方法
を確立した本発明の方法は、多くの有望な既存の誘導体
に対しても適用が可能である。The camptothecin derivative represented by the formula (I) according to the present invention has anticancer activity, and the present invention has established a method for efficiently chemically modifying the hydroxyl group at position 20 of camptothecin. The method is also applicable to many promising existing derivatives.
以下に実施例によυ本発明を更に詳細に説明するが、本
発明は、かかる実施例に特定されるものではない。The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples.
実施例１ ２０−０−オレオイルカンプトテシンカンプ
トテシン（１ｍｍｏｌ）とオレイン酸（１ｍｍｏｌ）ジ
シクロへキシルカルボジイミド（１ｍｍｏり及び４−Ｎ
、Ｎ−ジメチルアミノピリジン（触媒量）を塩化メチレ
ンに溶解し、この混合物を室温で２４時間攪拌する。反
応混合物を減圧下に乾固し、残留物をフラッシュカラム
クロマトグラフィ（ｎ−ヘキサン、酢酸エチル、メタノ
ール、４：５．５：［１５）により精製すると標記化合
物を固体として７６％の収率で得る。ｍ、ｐ、 ７８℃
ｌＮＭＲ（２００Ｍｇ 、 ＣＤＣｌｓ） ：δ１８５
（３Ｈ，ｔ 、 Ｊ＝１２５）、ｏ、’？５（３Ｈ，
ｔ、 Ｊ＝１５Ｈｚ）、１．２５（２０Ｈ，ｂｒｏａｄ
ｓｉ −ｎｇｌｅｔ ）、１．６ （２Ｈ，ｍ ）、
１．９（４Ｈ，ｍ）、２．３５ （２Ｈ，ｍ）、２．４
５ （２Ｈ，ｔ、 Ｊ＝α２５Ｈｚ）、５．２５ （４
Ｈ，ｍ）、５．４＆５．７ （２Ｈ，ｄ、 Ｊ＝ Ｉ
Ｈｚ）、７．２２（ＩＨ，＆）、７．６８（Ｉ Ｈ，ｔ
、 Ｊ ＝０．５Ｈｚ）、７．８５ （ＩＨ，ｔ、 Ｊ
＝１５Ｈｚ）、７．９５ （Ｉ Ｈ，ｄ、 Ｊ＝１５Ｈ
ｚ）、δ２ （Ｉ Ｈ，ｄ、 Ｊ＝０．５Ｈｚ）、δ４
（Ｉ Ｈ，ｄ、 Ｊ＝ＣＪ、５Ｈｚ）。Example 1 20-0-oleoylcamptothecin Camptothecin (1 mmol) and oleic acid (1 mmol) dicyclohexylcarbodiimide (1 mmol and 4-N
, N-dimethylaminopyridine (catalytic amount) is dissolved in methylene chloride and the mixture is stirred at room temperature for 24 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by flash column chromatography (n-hexane, ethyl acetate, methanol, 4:5.5:[15]) to give the title compound as a solid in 76% yield. . m, p, 78℃
lNMR (200Mg, CDCls): δ185
(3H,t, J=125), o,'? 5 (3H,
t, J=15Hz), 1.25(20H, broad
si-nglet), 1.6 (2H,m),
1.9 (4H, m), 2.35 (2H, m), 2.4
5 (2H, t, J=α25Hz), 5.25 (4
H, m), 5.4 & 5.7 (2H, d, J= I
Hz), 7.22 (IH, &), 7.68 (I H, t
, J = 0.5Hz), 7.85 (IH,t, J
= 15Hz), 7.95 (I H, d, J = 15H
z), δ2 (I H, d, J=0.5Hz), δ4
(IH, d, J=CJ, 5Hz).
ＩＲ（ＣＨＣＩｓ 、 ｃｍ−’） ： １７６０．１
６８０．１６２０実施例２ ２０−０−（９’、 １０
’−ジヒドロキシ）ステアロイルカンプトテシン
実施例１で得られた２０−０−オレオイルカンプトテシ
ン（ｃＬ４７′ＩＬｒｒｗｌ）を、ピリジン（３ｍ／）
に溶解し、四酸化オスミウム（０，４ｍｍｔｒｌ ）を
加え、亜硫酸水素ナトリウム（１５７，５ｍ９） 、水
（２，６２ｍ／ ） 。IR (CHCIs, cm-'): 1760.1
680.1620 Example 2 20-0-(9', 10
'-dihydroxy)stearoylcamptothecin 20-0-oleoylcamptothecin (cL47'ILrrwl) obtained in Example 1 was dissolved in pyridine (3 m/).
Add osmium tetroxide (0,4 mm trl), sodium bisulfite (157,5 m9), water (2,62 m/).
ピリジン（１，７５ｍＱを加え、室温で４時間攪拌する
。Add pyridine (1.75 mQ) and stir at room temperature for 4 hours.
反応混合物が橙色になった後塩化メチレンで抽出する。After the reaction mixture turned orange, it was extracted with methylene chloride.
抽出物は、フラッシュカラムクロマトグラフィー（ｎ−
ヘキサン、酢酸エチル、メタノール、２ ： ７．５
： ０．５）によシ精製すると、標記化合物が白色の粉
末として得られる。収率４５％ｍ、ｐ、 ｊ０６℃”
ＮＭＲ（２００Ｍｚ、 ＣＤＣ１３） ：δ０．８５
（３Ｈ，ｔ、 Ｊ＝ｌ１２５Ｈｚ）、Ｑ、９５（３Ｈ，
ｔ、 Ｊ＝Ｑ、５Ｈ２）、１．３ （２４Ｈ，ｂｒｏａ
ｔｌ ５ｉｑｌｅｔ）、１．６（２Ｈ，ｆｆ１）、１．
８ （２Ｈ，ｕｎｒｅｓｏｌｖｅｄ ５１ｇｍ１）、２
．２ （２Ｈ。The extract was subjected to flash column chromatography (n-
Hexane, ethyl acetate, methanol, 2: 7.5
: Purification according to 0.5) gives the title compound as a white powder. Yield 45%m,p,j06℃”
NMR (200Mz, CDC13): δ0.85
(3H, t, J=l125Hz), Q, 95 (3H,
t, J=Q, 5H2), 1.3 (24H, broa
tl 5iqlet), 1.6 (2H, ff1), 1.
8 (2H, unresolved 51gm1), 2
．． 2 (2H.
ｍ）、２．４５ （２Ｈ，ｔ、 Ｊ＝ｆ１２５Ｈｚ）、
３．５（２，Ｈ，ｍ）、５．２５（２Ｈ，ｓ）、５．４
＆ ５．７ （２Ｈｔ ｄ、 ｔｗｏ ｄｏｕｂｌｅ
ｔｓ、 Ｊ＝ 、１１．Ｈｚ）、７．１８（１Ｈ９Ｓ）
、Ｚ６（ＩＨ，ｔ、 Ｊ＝１５Ｈ２）、７．７（ＩＨ，
ＬＪ＝ＣＬ５Ｈ２）、７．９ （ＩＨ，ｄ、 Ｊ＝０．
５Ｈｚ）、Ｃ１５’（ＩＨ，ｄ、 Ｊ＝ ０．５ Ｈｚ
）、Ｃ３５（ＩＨ，８）。m), 2.45 (2H, t, J=f125Hz),
3.5 (2, H, m), 5.25 (2 H, s), 5.4
& 5.7 (2Ht d, two double
ts, J= , 11. Hz), 7.18 (1H9S)
, Z6 (IH, t, J=15H2), 7.7 (IH,
LJ=CL5H2), 7.9 (IH, d, J=0.
5 Hz), C15'(IH, d, J= 0.5 Hz)
), C35 (IH, 8).
ＩＲ（ＣＨＣ１３，ｃｒｎ、−’） ：３６００．１７
８０．１７００．１６５０゜ＭＳ ： ６４７ （Ｍ＋
１ 、Ｃ３ｓＨｓ１０ｒＮｚ ）。IR (CHC13, crn, -'): 3600.17
80.1700.1650°MS: 647 (M+
1, C3sHs10rNz).
実施例３ ２０−０−リルオイルカンプトテシン実施例
１におけるオレイン酸に代えてリノール酸を用い、実施
例１と同様の操作により反応を行い、フラッシュカラム
クロマトグラフィー（ｎ−ヘキサン、酢酸エチル、１：
３）により精製することにより標記化合物を５９％の収
率で得た。ｍ、ｐ、 ８１℃
’ ＮＭＲ（２００ＭＺ 、 ＣＤＣ１３） ：δ０．
８５ （３Ｈ，ｔ、 Ｊ＝ ０．２５Ｈｚ）、０．９５
（３Ｈ，ｔ、 Ｊ＝ Ｑ、５Ｈ２）、１．２５ （１
４Ｈ，ｂｒｏａｃｌｓｉｎｇｉｅｔ ）、１．６５ （
２Ｈ，ｍ）、１．９５ （４Ｈ，ｍ）、２．２ （２Ｈ
。Example 3 20-0-Liluoylcamptothecin Using linoleic acid in place of oleic acid in Example 1, a reaction was carried out in the same manner as in Example 1, and flash column chromatography (n-hexane, ethyl acetate, 1:
3), the title compound was obtained in a yield of 59%. m, p, 81°C' NMR (200MZ, CDC13): δ0.
85 (3H, t, J= 0.25Hz), 0.95
(3H, t, J= Q, 5H2), 1.25 (1
4H, broaclsingiet), 1.65 (
2H, m), 1.95 (4H, m), 2.2 (2H
.
ｍ）、２．４５（２Ｈ，ｔ、 Ｊ＝０．２５Ｈｚ）、２
．７ （２Ｈ，Ｌ Ｊ＝０．２５Ｈｚ）、５．２５ （
６Ｈ，ｍ ）、５．４ ＆ ５．６５ （２Ｈ，ｔｗｏ
ｄｏｕｂｌｅｔｓ。m), 2.45 (2H, t, J=0.25Hz), 2
．． 7 (2H,L J=0.25Hz), 5.25 (
6H, m ), 5.4 & 5.65 (2H, two
doublets.
Ｊ＝ ＩＨ２） 、７．２ （ＩＨ，ｓ ）、７．６５
（ＩＨ，ｔ、 Ｊ＝０．５Ｈ２）、７．８（ＩＨ，ｔ
、 Ｊ＝０．５Ｈ２）、７．９５ （Ｉ Ｈ，ｄ、 Ｊ
＝ ０．５Ｈ２）、８．２ （ＩＨ，ｄ、 Ｊ＝０．５
Ｈｚ）、Ｃ３８（ＩＨ，８）。J = IH2), 7.2 (IH,s), 7.65
(IH, t, J=0.5H2), 7.8 (IH, t
, J=0.5H2), 7.95 (I H,d, J
= 0.5H2), 8.2 (IH, d, J=0.5
Hz), C38 (IH, 8).
ＩＲ（ＣＨＣ１３，ｃｍ−”） ： １７４５．１６７
０．１０００ＭＳ：６１０（Ｍ 、 Ｃ３８Ｈ４ｇＣ
５８Ｈ４゜実施例４ ２ｏ−ｏ−（４′、１ｏ′、１り
、１３′−テトラヒドロキシ）ステアロイルカンフトチ
シ
ン
実施例２における２０−０−オレオイルカンプトテシン
に代えて、実施例３で得られたリルオイルカンプトテシ
ンを用い、実施例２で述べた方法に準拠して反応を行い
、フラッシュカラムクロマトグラフィー（酢酸エチル、
メタノール、１：（Ｌｌ）により精製し、標記化合物を
５７チの収率で得た。ｍ、ｐ、 １０８℃
’ ＮＭＲ（２００Ｍｚ 、 ＣＤＣｌｓ ） ：δ（
１７８（３Ｈ＋ ｕｎｒｅｓｏｌｖｅｄｔｒｉｐｌｅｔ
）、（１９（３Ｈ，ｔ、 Ｊ＝０．５Ｈｚ）、１．２
５ （１４Ｈ，ｂｒｏａｄｓｉｎｇｌｅｔ）、１．６
（６Ｈ，ｍ）、１．８８ （２Ｈ，ｍ）、２．２ （２
Ｈ，ｆｉ）、２．４２ （２Ｈ，ｍ ）、３．５ （４
Ｈ，ｍ）、３．７５ （２Ｈ，ｍ）、４．１（２Ｈ，ｓ
）、５．２ （２Ｈ，ｓ ）、５．３５ ＆ ５．６２
（２Ｈ，ｔｗｏ ｄｏ−ｕｂｌｅｔｓ、 Ｊ＝ Ｉ
Ｈｚ）、７．１５（ＩＨ，ｓ）、７．６ （１Ｈ，ｔ、
Ｊ＝０．５Ｈ２）、７．７５（ＩＨ，ｔ、 Ｊ＝０．
５Ｈｚ）、７．９ （Ｉ Ｈ，ｄ、 Ｊ＝０．５Ｈｚ）
、Ｃ１５（ＩＨ，ｄ、 Ｊ＝ｌ１５Ｈｚ）、Ｃ３２（Ｉ
Ｈ，ｓ）。IR (CHC13, cm-”): 1745.167
0.1000MS:610(M, C38H4gC
58H4゜Example 4 2o-o-(4', 1o', 1-, 13'-tetrahydroxy)stearoylcamptothecin Instead of 20-0-oleoylcamptothecin in Example 2, the 20-0-oleoylcamptothecin obtained in Example 3 was used. The reaction was carried out according to the method described in Example 2 using lyluoylcamptothecin, followed by flash column chromatography (ethyl acetate,
Purification with methanol, 1:(Ll) afforded the title compound in a yield of 57. m, p, 108℃' NMR (200Mz, CDCls): δ(
178 (3H+ unresolved triplet
), (19 (3H, t, J=0.5Hz), 1.2
5 (14H, broadsinglet), 1.6
(6H, m), 1.88 (2H, m), 2.2 (2
H,fi), 2.42 (2H,m), 3.5 (4
H, m), 3.75 (2H, m), 4.1 (2H, s
), 5.2 (2H,s), 5.35 & 5.62
(2H, two do-ublets, J=I
Hz), 7.15 (IH, s), 7.6 (1H, t,
J=0.5H2), 7.75(IH,t, J=0.
5Hz), 7.9 (IH, d, J=0.5Hz)
, C15 (IH, d, J=l15Hz), C32 (I
H,s).
ＩＲ（ＣＨＣｉ３． ｃ−ｉ−’） ： ３４６０．１
７４５．１６７０．１６２０ 。IR (CHCi3.c-i-'): 3460.1
745.1670.1620.
実施例５ ２０−０−！）ルノイルヵンプトテシン実施
例１におけるオレイン酸に代えてリルン酸を用い、実施
例１と同様の操作により反応ヲ行い、フラッシュカラム
クロマトグラフィー（ｎ−ヘキサン、酢酸エチル、１：
３）にょシ精製することにより標記化合物を６０％の収
率で得た・ｍ、ｐ、 ７７℃
” ＮＭＲ（２００Ｍｚ 、 ＣＤＣ１３） ：δＱ、
９ （６Ｈ，ｍ）、１．２５（１０Ｈ，ｂｒｏａｄ ｓ
ｉｎｇｌｅｔ ）、１．６ （２Ｈ，ｍ、）、２．１
（６Ｈ，ｍ）、２．４５ （２Ｈ，ｍ ）、２．７５
Ｃ２Ｈ，ｍ）、５．２５ （８Ｈ，ｍ）、５．６５＆
５．６８ （２Ｈ，ｔｗｏ ｄｏｕｂｌｅｔｓ、 Ｊ＝
Ｉ Ｈ２）、７．２（ＩＨ，８）、７．６５ （ＩＨ
，ｔ、 Ｊ＝ＣＪ、５Ｈ２）、７．８ （ＩＨ，ｔ、
Ｊ＝０．５Ｈｚ ）、７．９２ （ＩＨ，ｄ、 Ｊ＝Ｃ
１，５Ｈｚ）、Ｃ２（ＩＨ，ｄ、 Ｊ＝０．５Ｈｚ）、
Ｃ３８（ＩＨ，ｓ）。Example 5 20-0-! ) Lunoylcamptothecin The reaction was carried out in the same manner as in Example 1 except that oleic acid in Example 1 was replaced with lylunic acid, and flash column chromatography (n-hexane, ethyl acetate, 1:
3) The title compound was obtained in 60% yield by purification. m, p, 77°C" NMR (200Mz, CDC13): δQ,
9 (6H, m), 1.25 (10H, broad s
inglet), 1.6 (2H,m,), 2.1
(6H, m), 2.45 (2H, m), 2.75
C2H, m), 5.25 (8H, m), 5.65&
5.68 (2H, two doublets, J=
I H2), 7.2 (IH, 8), 7.65 (IH
, t, J=CJ, 5H2), 7.8 (IH, t,
J=0.5Hz), 7.92 (IH, d, J=C
1.5Hz), C2 (IH, d, J=0.5Hz),
C38 (IH, s).
ＩＲ（、ＣＨＣ１３，Ｃ，７７Ｌ−”） ： １７５０
．１６７０．１６１０Ｍ５ ： ６０８ （Ｍ＋、
Ｃ３８Ｈ４４０５Ｎ２ ）。IR(,CHC13,C,77L-”): 1750
．． 1670.1610M5: 608 (M+,
C38H4405N2).
特許出願人 株式会社 ヤクルト本社Patent applicant: Yakult Honsha Co., Ltd.
Claims (1)
飽和の高級脂肪酸のアシル基であり、このアシル基は置
換基として水酸基を有していてもよい）で表わされるカ
ンプトテシンの誘導体。 ２）カンプトテシンと飽和もしくは不飽和の高級脂肪酸
とを塩基物質の存在下に、カルボジイミド化合物を縮合
剤として用いて処理してエステル化することを特徴とす
る一般式（II） ▲数式、化学式、表等があります▼（II） （式中、Ｒ＾２は飽和もしくは不飽和の高級脂肪酸のア
シル基を示す）で表わされるカンプトテシン誘導体の製
造法。 ３）前記のカルボジイミド化合物がジシクロヘキシルカ
ルボジイミドである請求項２記載のカンプトテシン誘導
体の製造法。 ４）前記の塩基物質が、４−Ｎ，Ｎ−ジメチルアミノピ
リジンである請求項２もしくは請求項３記載のカンプト
テシン誘導体の製造法。 ５）一般式（III）、 ▲数式、化学式、表等があります▼（III） （式中、Ｒ＾３は不飽和脂肪酸のアシル基を示す）で表
わされるカンプトテシン誘導体を四酸化オスミウムで処
理することを特徴とする一般式（IV） ▲数式、化学式、表等があります▼（IV） （式中、Ｒ＾４は、置換基として水酸基を有する飽和脂
肪酸のアシル基を示す）で表わされるカンプトテシン誘
導体の製造法。[Claims] 1) General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R^1 is an acyl group of a saturated or unsaturated higher fatty acid having 16 to 20 carbon atoms. and this acyl group may have a hydroxyl group as a substituent). 2) General formula (II) characterized by esterifying camptothecin and a saturated or unsaturated higher fatty acid in the presence of a basic substance using a carbodiimide compound as a condensing agent ▲Mathematical formula, chemical formula, table ▼(II) A method for producing a camptothecin derivative represented by the formula (wherein R^2 represents an acyl group of a saturated or unsaturated higher fatty acid). 3) The method for producing a camptothecin derivative according to claim 2, wherein the carbodiimide compound is dicyclohexylcarbodiimide. 4) The method for producing a camptothecin derivative according to claim 2 or 3, wherein the basic substance is 4-N,N-dimethylaminopyridine. 5) Treating a camptothecin derivative represented by general formula (III), ▲mathematical formula, chemical formula, table, etc.▼(III) (in the formula, R^3 represents an acyl group of an unsaturated fatty acid) with osmium tetroxide. Camptothecin represented by the general formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (wherein R^4 represents an acyl group of a saturated fatty acid having a hydroxyl group as a substituent) Method for producing derivatives.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63073426A JP2524803B2 (en) | 1988-03-29 | 1988-03-29 | Novel camptothecin derivative and method for producing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63073426A JP2524803B2 (en) | 1988-03-29 | 1988-03-29 | Novel camptothecin derivative and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01246287A true JPH01246287A (en) | 1989-10-02 |
| JP2524803B2 JP2524803B2 (en) | 1996-08-14 |
Family
ID=13517900
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63073426A Expired - Lifetime JP2524803B2 (en) | 1988-03-29 | 1988-03-29 | Novel camptothecin derivative and method for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2524803B2 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997028165A1 (en) * | 1996-01-30 | 1997-08-07 | The Stehlin Foundation For Cancer Research | Derivatives of camptothecin for use in treating cancer |
| WO2002056885A1 (en) * | 2001-01-18 | 2002-07-25 | California Pacific Medical Center | Camptothecin derivatives |
| US6486320B2 (en) | 2000-09-15 | 2002-11-26 | Aventis Pharma S.A. | Preparation of camptothecin and of its derivatives |
| US6506734B1 (en) | 1997-05-14 | 2003-01-14 | Bayer Aktiengesellschaft | 20(S) camptothecin glycoconjugates |
| US6562834B2 (en) | 2000-10-27 | 2003-05-13 | Aventis Pharma S. A. | Combination comprising camptothecin and a stilbene derivative for the treatment of cancer |
| US6664242B2 (en) | 2000-02-28 | 2003-12-16 | Aventis Pharma S.A. | Composition and method comprising CPT-11 and a pyrimidine derivative for the treatment of cancer |
| KR100474496B1 (en) * | 1996-10-30 | 2005-09-30 | 다나베 세이야꾸 가부시키가이샤 | S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof |
| US6960596B2 (en) | 2000-03-17 | 2005-11-01 | Aventis Pharma S.A. | Composition comprising camptothecin or a comptothecin derivative and a platin derivative for the treatment of cancer |
| WO2005118612A1 (en) * | 2004-06-04 | 2005-12-15 | Sonus Pharmaceuticals, Inc. | Cholesterol/bile acid/bile acid derivative-modified therapeutic anti-cancer drugs |
-
1988
- 1988-03-29 JP JP63073426A patent/JP2524803B2/en not_active Expired - Lifetime
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997028165A1 (en) * | 1996-01-30 | 1997-08-07 | The Stehlin Foundation For Cancer Research | Derivatives of camptothecin for use in treating cancer |
| EP1829880A3 (en) * | 1996-01-30 | 2008-03-26 | The Stehlin Foundation For Cancer Research | Derivatives of camptothecin for use in treating cancer |
| KR100474496B1 (en) * | 1996-10-30 | 2005-09-30 | 다나베 세이야꾸 가부시키가이샤 | S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof |
| US6506734B1 (en) | 1997-05-14 | 2003-01-14 | Bayer Aktiengesellschaft | 20(S) camptothecin glycoconjugates |
| US6664242B2 (en) | 2000-02-28 | 2003-12-16 | Aventis Pharma S.A. | Composition and method comprising CPT-11 and a pyrimidine derivative for the treatment of cancer |
| US6960596B2 (en) | 2000-03-17 | 2005-11-01 | Aventis Pharma S.A. | Composition comprising camptothecin or a comptothecin derivative and a platin derivative for the treatment of cancer |
| US6486320B2 (en) | 2000-09-15 | 2002-11-26 | Aventis Pharma S.A. | Preparation of camptothecin and of its derivatives |
| US6562834B2 (en) | 2000-10-27 | 2003-05-13 | Aventis Pharma S. A. | Combination comprising camptothecin and a stilbene derivative for the treatment of cancer |
| WO2002056885A1 (en) * | 2001-01-18 | 2002-07-25 | California Pacific Medical Center | Camptothecin derivatives |
| WO2005118612A1 (en) * | 2004-06-04 | 2005-12-15 | Sonus Pharmaceuticals, Inc. | Cholesterol/bile acid/bile acid derivative-modified therapeutic anti-cancer drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2524803B2 (en) | 1996-08-14 |
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