WO2006116897A1

WO2006116897A1 - Diterpenes from euphorbia kansui and their use

Info

Publication number: WO2006116897A1
Application number: PCT/CN2005/000610
Authority: WO
Inventors: Liyan Wang; Susumu Kitanaka; Shohei Miyata
Original assignee: Nihon University
Priority date: 2005-04-30
Filing date: 2005-04-30
Publication date: 2006-11-09

Abstract

Novel diterpenes with antitumor activity of formula (I), wherein R1 ~ R3 represent aliphatic group; or represent group of RCO-, in which R represents aliphatic group, aryl, or heteroaryl. The compounds of the present invention are prepared by extracting roots of euphorbia kansui with organic solvent (chloroform, ethyl acetate and butanol) and treating the extract by conventional methods. The compounds of the present invention have cell proliferation inhibiting activity, and can inhibit the proliferation of specific cancer cell lines via inhibition of topoisomerase. These compounds can be used for preparing medicaments for treating malignant tumor.

Description

从甘遂中提取的二萜类化合物及其用途技术械 Diterpenoids extracted from Ganzi and their uses

本发明涉及从药用植物甘遂（学名： Euphorbia kansui L. ) 中分离提取二萜类化合物，特别涉及具有抑制拓朴异构酶 II活性的二萜类化合物及其用途。皆景技术 The present invention relates to the separation and extraction of diterpenoids from the medicinal plant Ganzi (scientific name: Euphorbia kansui L.), and more particularly to diterpenoid compounds having activity for inhibiting topoisomerase II and uses thereof. Scenery technology

甘遂（学名： Euphorbia ka讓 i L.、職, 分布在中国西北部。甘遂在中国被用于治疗慢性支气管炎、支气管哮喘等呼吸道疾病及食道癌、乳腺癌等恶性肿瘤的医治。甘遂成分的研究始于 1943年，现在已经有十多种二萜和三萜被发现。这些成分中，发现若干二萜类化合物具有抗癌作用、抗病毒作用和细胞毒性作用，而备受瞩目。 Ganzi (scientific name: Euphorbia ka let i L., position, distributed in northwestern China. Ganzi is used in China to treat respiratory diseases such as chronic bronchitis and bronchial asthma, as well as the treatment of malignant tumors such as esophageal cancer and breast cancer. The study of bismuth ingredients began in 1943, and now more than ten kinds of diterpenoids and triterpenoids have been discovered. Among these ingredients, several diterpenoids have been found to have anticancer, antiviral and cytotoxic effects, and have attracted much attention. .

Kupchan(S.M.Kupchan)等发现，从 Euphorbia esula L. 中提取的如下结构式（1 )所示的巨大戟二萜醇衍生物对老鼠的？一338淋巴性白血病具有活性（非专利文献 1 )。 Kupchan (S.M. Kupchan) et al. found that the ingenol derivative represented by the following structural formula (1) extracted from Euphorbia esula L. was used in mice? One 338 lymphocytic leukemia is active (Non-Patent Document 1).

吴（Tian- Shung Wu )等发现，从甘遂（ Euphorbia kansui L )的根部提取的甘遂宁 A (如下式（ 2 ) )和甘遂宁 B (如下式（ 3 ) )经过体内（ P- 388 ) 试验，证明具有活性（非专利文献 2 )。

Wu (Tian- Shung Wu) found that from the root of Euphorbia kansui L The extracted ginseng A (the following formula (2)) and gansin B (the following formula (3)) were tested by the in vivo (P-388) test to prove activity (Non-Patent Document 2).

Magdalena Blanco- Molina等记载了如下式（4 ) 所表示的巨大戟二萜醇衍生物诱导 Jurkat细胞的细胞凋亡（非专利文献 3 )。 Magdalena Blanco-Molina et al. describe the induction of apoptosis in Jurkat cells by the indole sterol derivative represented by the following formula (4) (Non-Patent Document 3).

RaO RaO

[非专利文献 1] [Non-Patent Document 1]

S.Morris Kupc an,et.al.,Science,VoL191,pp.571-572,13₃Feb.,1976 [非专利文献 2] S. Morris Kupc an, et. al., Science, VoL 191, pp. 571-572, 13 ₃ Feb., 1976 [Non-Patent Document 2]

Tian-Shuang Wu,et.al.,J.Nat.prod.,Vol.54,No.3,pp.823-829,1991 [非专利文献 3] Tian-Shuang Wu, et.al., J. Nat. prod., Vol. 54, No. 3, pp. 823-829, 1991 [Non-Patent Document 3]

Magdalena Blanco- Molina, et.al..,Chemisti &Biology，8/8，pp.767- 768， 2001 根据拓朴酶诱导 DNA断裂机制的不同,将 DNA拓朴酶分为两类，分别称为拓朴酶 I ( Topo I ) 和拓朴酶 II ( Τορο II) 。拓朴酶共价结合于双链 DNA，分别引起瞬间单链（ Topo I ) 或双链（ Topo II) 断裂，使另外的完整链穿过切口，再连接断裂链，由此改变 DNA的拓朴结构，使 D NA发挥正常的生理功能。 Topo I包括细菌 Topo I、 III、真核生物 T opo I、111和逆旋转酶。它是 100kD 的单体蛋白质，由一个单基因编码。 Topo II包括细菌 DNA旋转酶、细菌 Topo IV和真核 Topo II，另外噬菌体 T4和某些病毒如非洲猪热病毒的拓朴酶也属 II类拓朴酶。 Topo Π是多亚基蛋白质，真核生物 Topo II由两个亚基组成，各为 160 ~ 180kD。有报道在真核生物线粒体和叶绿体中也有拓朴酶存在。 Topo I、 II在维持 DNA拓朴结构方面有共同之处，磷酸化可增强其活性。对一种类型拓朴酶的抑制导致另一种类型拓朴酶活性的增加。例如，如果 Topo I被 Top 0 I活性药物作用，则 Topo II活性代偿性增加，使 DNA合成和细胞生存。但二者之间仍有一些主要差异： ① Topo I对生活细胞并不是必不可少的，不是细胞周期特异性酶，即它的活性不随细胞生长的不同阶段而变化； Topo II为细胞所必需,且在对数期和快速生长的肿瘤中活性最高。② Topo I诱导单链 DNA断裂，而 Topo II诱导双链 DNA断裂。 ③ Topo I的功能不依赖于 ATP，而 Topo II依赖于 ATP。 Magdalena Blanco- Molina, et.al.., Chemisti & Biology, 8/8, pp. 767- 768, 2001 According to the different mechanisms of DNA cleavage induced by topotems, DNA topology enzymes are divided into two categories, respectively called extension Topo I and Topozyme II (Τορο II). Topotease covalently binds to double-stranded DNA, causing a transient single-strand (Topo I ) or double-stranded ( Topo II ) cleavage, allowing another intact strand to pass through the nick and then join the cleavage strand, thereby altering the topology of the DNA The structure allows the DA to function as a normal physiological function. Topo I includes bacteria Topo I, III, eukaryotes T opo I, 111 and inverse gyrase. It is a 100kD monomeric protein encoded by a single gene. Topo II includes bacterial DNA gyrase, bacterial Topo IV and eukaryotic Topo II. In addition, phage T4 and certain viruses such as the porcine heat virus of the African porcine fever virus are also class II topologies. Topo Π is a multi-subunit protein, and eukaryote Topo II consists of two subunits, each 160-180kD. It has been reported that topological enzymes are also present in mitochondria and chloroplasts of eukaryotes. Topo I and II have in common in maintaining DNA topology, and phosphorylation enhances their activity. Inhibition of one type of topology enzyme results in an increase in the activity of another type of topology enzyme. For example, if Topo I is acted upon by Top 0 I active drugs, Topo II activity is compensatoryly increased, resulting in DNA synthesis and cell survival. However, there are still some major differences between the two: 1 Topo I is not essential for living cells, not cell cycle-specific enzymes, ie its activity does not change with different stages of cell growth; Topo II is required for cells And is the most active in log phase and fast growing tumors. 2 Topo I induces single-strand DNA breaks, while Topo II induces double-strand DNA breaks. 3 Topo I's functionality does not depend on ATP, while Topo II relies on ATP.

由于肿瘤细胞具有快速增殖的特性，其 TOPO II的含量及活性远远高于正常体细胞，因此抑制 TOPO II活性能起到阻止肿瘤细胞快速生长增殖，进而杀死肿瘤细胞的作用。 TOPO II已成为抗癌药物的重要作用靶点。通常将主要以 TOPO II为靶点的药物统称为 TOPO II抑制剂。近年来，对以 TOPO II为靶点的抗癌药物及其作用方式的研究取得了很大的进展。 Due to the rapid proliferation of tumor cells, the content and activity of TOPO II is much higher than that of normal somatic cells, so inhibition of TOPO II activity can prevent rapid growth of tumor cells. Colonization, which in turn kills the role of tumor cells. TOPO II has become an important target for anticancer drugs. Drugs that primarily target TOPO II are collectively referred to as TOPO II inhibitors. In recent years, great progress has been made in the study of anticancer drugs targeting TOPO II and their modes of action.

有学者研究了喜树碱的 S期细胞毒作用。这一作用需共价 Topo I DNA复合物的形成与 DNA复制。 DNA合成和药物一 Topo I— DNA 复合物间的相互作用在复制 DNA上引起了 DSBs 的形成。即如果断裂复合物遇上了移动的复制叉，此复制叉若有产生 DNA双链断裂的序列，则可产生潜在的致死性损伤。三联复合物存在时间越长，与移动的复制叉致死性相互作用的可能性越大。 Topo II抑制剂亦有相似机制。 Topo II除在 DNA合成中起作用外，还构成有丝***染色体支架的一部分。酶位于染色质环的底部，并将基质相关区锚定于支架上。有些药物能作用于染色体环底部的 Topo II，它们的作用不需要 DNA复制。当从染色质上释放 (或交换) DNA片段时，留下的染色质环形态上是完整的。染色质环底部亚单位的交换使肿瘤细胞致死或致突变。 Some scholars have studied the S phase cytotoxicity of camptothecin. This effect requires the formation of covalent Topo I DNA complexes and DNA replication. The interaction between DNA synthesis and drug-Topo I-DNA complexes causes the formation of DSBs on replicating DNA. That is, if the cleavage complex encounters a moving replication fork, the replication fork can produce potentially lethal damage if it has a sequence that produces a DNA double-strand break. The longer the triple complex exists, the greater the likelihood of interaction with the moving replication fork lethality. Topo II inhibitors have similar mechanisms. In addition to its role in DNA synthesis, Topo II forms part of a mitotic chromosome scaffold. The enzyme is located at the bottom of the chromatin loop and anchors the matrix-associated region to the scaffold. Some drugs can act on Topo II at the bottom of the chromosome ring, and their function does not require DNA replication. When the DNA fragment is released (or exchanged) from the chromatin, the remaining chromatin ring is morphologically intact. Exchange of the subunits of the chromatin loop bottom causes lethal or mutagenic tumor cells.

Topo II抑制剂可在细胞周期任一时相引起染色体畸变，叫做" S― 非依赖性，：在 S 期用 Topo II抑制剂处理细胞还会引起姐妹染色单体交换 (SCEs) 。相反，只有用 Topo I抑制剂喜树碱处理处于 S 期或 G2期细胞时才引起染色体畸变，而对 G1 期细胞无影响。在 S期给药时,喜树碱 —Topo I - DNA复合物引起的复制叉断裂所形成的 DSBs 除会引起染色体畸变外，还可产生 SCEs。无疑，染色体畸变和 (或） SCEs都可能导致肿瘤细胞的最终死亡。研究发现紫杉醇也有类似 TOPO II毒剂的作用,而且作用方式独特，在低浓度时抑制 TOPO II的解旋，而在高浓度时却促进其解旋，自从 20 年前 TOPO II被发现以来，研究者已经充分认识到 TOPO II在 DNA代谢、染色体重组和细胞***过程中具有重要的作用。 TOPO II已成为抗癌药物细胞内重要的作用靶点，几乎每一种癌症全身化疗的治疗方案都集中于或包括以其为靶点的药物。目前,世界上有上百种以 TOPO II 为靶点的抗癌药物处于临床前或临床研究。另一方面，尽管对 TOPO II的认识有了长足的进步，但是仍有许多问题尚待深入研究和探讨：如 TOPO II α和 β的确切功能及分工； TOPO II催化抑制剂直接抑制酶活力的确切机制；药物的不同作用机制对临床应用的影响; TOPO II催化抑制剂和 TOPO II毒剂间的相互作用关系等。随着对 TOPO II生理功能的逐渐了解，以及对以 TOPO II为作用靶点的药物作用机制研究的不断深入，我们将能得到特异性更高、作用更强、不良反应更小的 ΤΟΡΟ Π抑制剂，为肿瘤治疗提供更合理、更有效的方案。 Topo II inhibitors can cause chromosomal aberrations at any stage of the cell cycle, called "S-independent,: treatment of cells with Topo II inhibitors in S phase also causes sister chromatid exchange (SCEs). Instead, only When the Topo I inhibitor camptothecin is treated with S phase or G2 phase cells, it causes chromosomal aberrations and has no effect on G1 phase cells. In the S phase, the replication fork caused by camptothecin-Topo I-DNA complex In addition to causing chromosomal aberrations, DSBs formed by cleavage can also produce SCEs. Undoubtedly, chromosomal aberrations and/or SCEs may lead to the ultimate death of tumor cells. The study found that paclitaxel also has a similar effect to TOPO II, and it has a unique mode of action, inhibiting the unwinding of TOPO II at low concentrations and promoting its unwinding at high concentrations, since the discovery of TOPO II 20 years ago, researchers It has been well recognized that TOPO II plays an important role in DNA metabolism, chromosome recombination and cell division. TOPO II has become an important target for intracellular anticancer drugs. The treatment regimen of systemic chemotherapy in almost every cancer is focused on or includes drugs targeted at it. At present, there are hundreds of anti-cancer drugs targeting TOPO II in the world in preclinical or clinical research. On the other hand, although the understanding of TOPO II has made great progress, there are still many problems to be further studied and discussed: such as the exact function and division of TOPO II α and β; TOPO II catalytic inhibitor directly inhibits enzyme activity The exact mechanism; the effect of different mechanisms of action on clinical application; the interaction between TOPO II catalytic inhibitors and TOPO II agents. With the gradual understanding of the physiological functions of TOPO II and the deepening of research on the mechanism of action of drugs targeting TOPO II, we will be able to obtain higher specificity, stronger effects, and less adverse reactions. Agents provide a more reasonable and effective solution for cancer treatment.

Topo II是 DNA代谢必不可少的核酶，是化学治疗的重要靶酶。但肿瘤对 Topo II抑制剂有多种抗药机制，会导致化疗失败。因此，迫切需要设计发展新的 Topo II抑制剂。发明内容 Topo II is an essential ribozyme for DNA metabolism and an important target enzyme for chemotherapy. However, tumors have multiple mechanisms of resistance to Topo II inhibitors, which can lead to chemotherapy failure. Therefore, there is an urgent need to design and develop new Topo II inhibitors. Summary of the invention

为寻找到更有效的拓朴异构酶 II抑制剂，本发明提供了从甘遂中提取的化合物，其通式为下述式（1 ):

In order to find a more potent topoisomerase II inhibitor, the present invention provides a compound extracted from kansui having the formula: (1):

式中 Ri至 R₃可以相同或不同，表示氢原子、直链或含支链的饱和或不饱和取代或未取代的脂肪族取代基；或表示用通式 RCO -表示的取代基，其中， R表示直链或含支链的饱和或不饱和取代或未取代脂肪族取代基，或者取代或未取代的芳基或杂芳取代基。 Wherein Ri to R ₃ may be the same or different and represent a hydrogen atom, a linear or branched saturated or unsaturated substituted or unsubstituted aliphatic substituent; or a substituent represented by the formula RCO - wherein R represents a linear or branched saturated or unsaturated substituted or unsubstituted aliphatic substituent, or a substituted or unsubstituted aryl or heteroaryl substituent.

在本发明通式 (I)中所记载的二萜类化合物优选 The diterpenoid compound described in the general formula (I) of the present invention is preferably

Ri,R2=H,R3=CO-(CH=CH)2-(CH₂)4-CH3(^ Ri, R2=H, R3=CO-(CH=CH)2-(CH ₂ )4-CH3(^

或

or

或 R =CO- (CH=CH)₂-(CH₂)4-CH₃C^¾R₂,R₃=H Or R = CO- (CH=CH) ₂ -(CH ₂ )4-CH ₃ C^3⁄4R ₂ , R ₃ =H

或 Or

或

or

或， =11,1 ₃=(30-(€! )₈- CH₃ Or, =11,1 ₃ =(30-(€! ) ₈ - CH ₃

或

or

通式（ II ) 中所表示的二萜类化合物： H H Diterpenoids represented by the formula (II): HH

( II ) (II)

式（ II )中

， Ri =CO- (CH=CH)2- (CH₂)4- C C©^。 In formula (II)

, Ri =CO- (CH=CH)2- (CH ₂ )4- CC©^.

如上所述的化合物，为拓朴异构酶 II抑制剂。 The compound as described above is a topoisomerase II inhibitor.

如上所述的化合物，为仅具有抑制拓朴异构酶 II活性而不具有细胞凋亡活性的拓朴异构酶 II抑制剂。 The compound as described above is a topoisomerase II inhibitor having only the activity of inhibiting topoisomerase II and having no apoptotic activity.

如上所述的化合物，在制备治疗与拓朴异构酶 II活性有关的疾病的药物中的用途。 The use of a compound as described above for the manufacture of a medicament for the treatment of a disease associated with topoisomerase II activity.

如上所述的化合物，在制备通过抑制拓朴异构酶 II活性而治疗疾病的药物中的用途。 The use of a compound as described above for the preparation of a medicament for treating a disease by inhibiting the activity of topoisomerase II.

如上所述的化合物，在制备通过抑制动物细胞繁殖而治疗疾病的药物中的用途。 The use of a compound as described above for the preparation of a medicament for treating a disease by inhibiting the proliferation of animal cells.

如上所述的化合物，在制备***疾病的药物中的用途。 A compound as described above for use in the manufacture of a medicament for the treatment of a neoplastic disease.

如上所述的用途，所述的肿瘤为实体瘤。 For use as described above, the tumor is a solid tumor.

如上所述的用途，所述的肿瘤为乳腺癌。 For the use as described above, the tumor is breast cancer.

如上所述的用途，所述的肿瘤为食道癌。 For the use as described above, the tumor is esophageal cancer.

一种药物組合物，包括如上所述的化合物为有效成分和药物可接受的载体和 /或助剂。 A pharmaceutical composition comprising a compound as described above as an active ingredient and a pharmaceutically acceptable carrier and/or adjuvant.

一种联合制剂盒，可以同时、分别或顺序使用非抑制拓朴异构酶活性的抗癌药物和有效成分包括如上所述的化合物的药物组合物。 A combined preparation kit for simultaneous, separate or sequential use of non-inhibiting topoisomerase activity The sexual anticancer drug and active ingredient include a pharmaceutical composition of the compound as described above.

一种从甘遂中提取的如尚所述的化合物的盐、对映体、外消旋体、互变异构体或生理官能衍生物。可用于制备***疾病药物。 A salt, enantiomer, racemate, tautomer or physiologically functional derivative of a compound as described above, extracted from the genus Ganzi. It can be used to prepare drugs for treating tumor diseases.

通式（ I ) 的化合物对非洲爪蛙的后期细胞胚的动物极细胞显示出了细胞***抑制活性，可以作为食道癌、乳腺癌等恶性肿瘤的治疗药物来使用。 The compound of the formula (I) exhibits cell division inhibitory activity against animal pole cells of the late cell embryo of the African clawed frog, and can be used as a therapeutic drug for malignant tumors such as esophageal cancer and breast cancer.

本发明的化合物是有效对抗恶性肿瘤的新型二萜类化合物，可以用于恶性肿瘤对抗药物。 The compounds of the present invention are novel diterpenoids effective against malignant tumors and can be used against malignant tumors against drugs.

一般经过拓朴 Π阻碍剂处理后，细胞会导致坏死，本分明中拓朴异构酶 II抑制剂在抑制细胞繁殖的过程中，其抑制浓度完全不会引起细胞繁殖坏死的特性，作为细胞***和癌症发病机理研究的试剂具有很高的价值。 Generally, after treatment with a topping inhibitor, the cells cause necrosis. In the process of inhibiting cell proliferation, the inhibitory concentration of the topoisomerase II inhibitor does not cause cell proliferation and necrosis at all, as cell division and cancer. The reagents for pathogenesis studies are of high value.

我们从巨大戟二萜醇衍生物中发现了多种化合物，例如①抑制拓朴异构酶 II活性、不抑制细胞繁殖， ②抑制细胞繁殖、不抑制拓朴异构酶 II活性， ③抑制拓朴异构酶 II活性也抑制细胞繁殖。 We have found a variety of compounds from the indole derivatives, such as 1 inhibition of topoisomerase II activity, no inhibition of cell proliferation, 2 inhibition of cell proliferation, inhibition of topoisomerase II activity, 3 inhibition of topoisomerase II activity It also inhibits cell proliferation.

到现在，本发明出现为止被发现的所有拓朴异构酶 II抑制剂除具有抑制拓朴异构酶 II活性外 , 还具有细胞凋亡的活性。 Up to now, all of the topoisomerase II inhibitors which have been discovered since the present invention have apoptosis activity in addition to the activity of topoisomerase II.

与此相反地，我们发现了巨大戟二萜醇衍生物仅抑制拓朴异构酶 II 活性、不具有细胞凋亡地活性，所以发现巨大戟二萜醇衍生物是新的拓朴异构酶 II抑制剂。 In contrast, we found that the ingenol derivative inhibits only topoisomerase II activity and has no apoptotic activity, so it was found that the ingenol derivative is a novel topoisomerase II inhibitor.

本发明中拓朴异构酶 II抑制剂的一种^ "生物中含有专门针对乳癌细胞扩散的特殊化合物。本发明的拓朴异构酶 II抑制剂无论作为在遗传信息的发现中分析拓朴 Π功能的试剂，还是作为针对拓朴 II亢进的癌分子的抗癌剂都是令人期待的巨大戟二萜醇衍生物群。具体实施方式 In the present invention, a topoisomerase II inhibitor contains a specific compound specifically for the spread of breast cancer cells. The topoisomerase II inhibitor of the present invention acts as a genetic The reagents for analyzing the function of the topography in the discovery of interest, or the anticancer agents for the cancer molecules that are aimed at the topology II are all expected large populations of sterol derivatives. detailed description

通式（ I )所示化合物的 1^至 R₃中，作为脂肪族基优选直链或含支链的饱和或不饱和的含有 1 ~ 30个碳原子的芳基，更优选含有 1 ~ 16 的碳原子的脂肪族基。作为脂肪族基的取代基，可以列举如卤素原子、羟基、醚基、羰基、、氨基、酰氨基等。 In the compound 1 to R ₃ of the compound of the formula (I), the aliphatic group is preferably a linear or branched saturated or unsaturated aryl group having 1 to 30 carbon atoms, more preferably 1 to 16 An aliphatic group of carbon atoms. Examples of the substituent of the aliphatic group include a halogen atom, a hydroxyl group, an ether group, a carbonyl group, an amino group, an acylamino group and the like.

衍生有通式 RCO-表示的基，其原来的羧酸中，作为 R是烃基的羧酸可以列举如醋酸、丙酸、丁酸、 2, 3 -二甲基丁酸、辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸等碳原子数为 1 ~ 16的饱和脂肪酸， 2, 4-癸二酸等的碳原子数为 1 ~ 16的不饱和脂肪酸等。作为 R是芳基的羧酸，则可以列举如安息香酸、邻苯二甲酸、水杨酸、邻氨基苯甲酸等芳香族羧酸。作为 R为杂芳基的羧酸可以列举如糠酸、噻吩曱酸、吡啶羧酸、烟酸、异烟酸等的芳杂环羧酸。作为芳基以及杂芳基的取代基可列举如卤素原子、羟基、醚基、羰基、羧基、氨基、酰氨基等。 Derived from the group represented by the formula RCO-, in the original carboxylic acid, the carboxylic acid having R as a hydrocarbon group may, for example, be acetic acid, propionic acid, butyric acid, 2,3-dimethylbutyric acid, octanoic acid or decanoic acid. A saturated fatty acid having 1 to 16 carbon atoms such as lauric acid, myristic acid or palmitic acid, and an unsaturated fatty acid having 1 to 16 carbon atoms such as 2,4-sebacic acid. Examples of the carboxylic acid wherein R is an aryl group include aromatic carboxylic acids such as benzoic acid, phthalic acid, salicylic acid and anthranilic acid. The carboxylic acid wherein R is a heteroaryl group may, for example, be an aromatic heterocyclic carboxylic acid such as citric acid, thiopheneic acid, pyridinecarboxylic acid, nicotinic acid or isonicotinic acid. Examples of the substituent of the aryl group and the heteroaryl group include a halogen atom, a hydroxyl group, an ether group, a carbonyl group, a carboxyl group, an amino group, an acylamino group and the like.

实施例 1中国产甘遂 15kg (学名： Euphorbia kansui L. )用 60 %的乙醇配成 45L的溶液，将此进行两次加热浸提后，在减压下浓缩得到 1200g提取物。将此溶解于 4L水中，用氯仿、乙酸乙酯、及丁醇各 4 L, 依次各自提取 3次。将其減压浓缩后，得到氯仿馏分 165g, 乙酸乙酯馏分 23g，丁醇馏分 64g。 Example 1 Chinese cabbage glutinous rice 15 kg (scientific name: Euphorbia kansui L.) was formulated into a 45 L solution with 60% ethanol, and this was subjected to two heating leaching, followed by concentration under reduced pressure to obtain 1200 g of an extract. This was dissolved in 4 L of water, and each of them was extracted three times with 4 L of chloroform, ethyl acetate and butanol. After concentrating under reduced pressure, 165 g of a chloroform fraction, 23 g of ethyl acetate fraction and 64 g of a butanol fraction were obtained.

从上述各馏分中，取氯仿镏分的浓缩提取物 150g,用硅胶层析柱（W ako gel C- 200、和光纯药社制、 13x22cm, 洗脱剂为正己烷：乙酸乙酯体系，用乙酸乙酯浓度 0。/。、 1 %、 2 %、 3 %、 5 %、 1 0 %、 2 0 %、 30 %、 50 %依次展开），分离出 1 - 9的 9个组分。 From each of the above fractions, 150 g of concentrated extract of chloroform aliquot was taken, and a silica gel column (W) was used. Ako gel C-200, manufactured by Wako Pure Chemical Industries, Ltd., 13x22cm, eluent is n-hexane: ethyl acetate system, with ethyl acetate concentration 0. /. , 1%, 2%, 3%, 5%, 10%, 20%, 30%, 50% are sequentially expanded), and 9 components of 1 - 9 are separated.

实施例 2将实施例 1中得到的洗脱液组分 7, 用反相柱（ODS- 751 5-12A, SSC社制、洗脱剂：水—甲醇体系、用水分浓度为 70 %、 50 %、 40 %、 3 0 %、 1 0 %依次展开）进行分离。取水分约 40%附近洗脱出的溶液，用正相 HPLC进行分离。柱使用硅胶层析柱 ( YMC - P a c k S I L - 06、 YMC社制、 1 50 x 20 mm), 流动相使用正己烷：乙酸乙酯 =4: 1, 流速 4mL/min (室温）使其洗脱，利用 U V ( 210nm )分离出在保留时间 13分、 14分、 20分、 27分、 29分洗脱的峰。将这些峰的洗脱液减压浓缩 , 得到化合物 1， 2， 3， 4, 8 ( 12. lmg,22.1mg, 13.4mg, 14.1mg, 2.1mg)的无色油状物质。取水分浓度约 30%附近洗脱的溶液，使用反相 HPLC进行分离。柱使用硅胶层析柱 ( YMC - P a c k S I L- 06、 YMC社制、 1 50x20 mm )、流动相使用正己烷：乙酸乙酯 =5: 1, 流速 4mL/min (室温）使其洗脱，利用 UV (210nm)分离出在保留时间 11分、 13分、 21分、 27分洗脱的峰。将这些峰的洗脱液减压浓缩，得到化合物 5、 6、 7、 9 ( ll.lmg, 9.8mg, 4.1mg, 12.3mg)的无色油状物制。取水分约 50%附近洗脱的溶液，用正相 HPLC进行分离。柱使用硅胶层析柱 ( YMC - P a c k S I L - 06、 YMC社制、 1 50 x20 mm), 流动相使用正己烷：乙酸乙酯 =6: 1、流速 4mL/min (室温）使其洗脱，利用 UV(210nm) 分离出在保留时间 8分、 14分、 16分洗脱的峰。将这些峰的洗脱液减压浓缩，得到化合物 10、 11、 12 ( 26.1mg, 13.5mg, 19.1mg )的无色油状物质。 Example 2 The eluent component 7 obtained in Example 1 was subjected to a reverse phase column (ODS-751 5-12A, manufactured by SSC, eluent: water-methanol system, with a water concentration of 70%, 50). %, 40%, 30%, and 10% are sequentially expanded to perform separation. A solution eluted near about 40% of water was taken and separated by normal phase HPLC. The column was sieved on a silica gel column (YMC-P ack SIL-06, manufactured by YMC, 1 50 x 20 mm), and the mobile phase was treated with n-hexane: ethyl acetate = 4: 1, and the flow rate was 4 mL/min (room temperature). The peak eluted at a retention time of 13 minutes, 14 minutes, 20 minutes, 27 minutes, and 29 minutes was separated by UV (210 nm). The eluate of these peaks was concentrated under reduced pressure to give compound 1, 2, 3, 4, 8 ( 12. lmg, 22.1 mg, 13.4 mg, 14.1 mg, 2.1 mg) as a colorless oily material. A solution eluted near a water concentration of about 30% was taken and separated using reverse phase HPLC. The column was sieved on a silica gel column (YMC-P ack SI L- 06, manufactured by YMC, 1 50×20 mm), and the mobile phase was purged with n-hexane: ethyl acetate = 5:1, at a flow rate of 4 mL/min (room temperature). The peak eluted at a retention time of 11 minutes, 13 minutes, 21 minutes, and 27 minutes was separated by UV (210 nm). The eluate of these peaks was concentrated under reduced pressure to give compound 5, 6, 7, 9 (11.lmg, 9.8mg, 4.1mg, 12.3mg) as a colorless oil. A solution eluted near about 50% of water was taken and separated by normal phase HPLC. The column was chromatographed on a silica gel column (YMC - P ack SIL - 06, manufactured by YMC, 1 50 x 20 mm), and the mobile phase was eluted with n-hexane: ethyl acetate = 6:1, at a flow rate of 4 mL/min (room temperature). The peak eluted at retention time of 8 minutes, 14 minutes, and 16 minutes was separated by UV (210 nm). Decompress the eluates of these peaks Concentration gave Compound 10, 11 and 12 ( 26.1 mg, 13.5 mg, 19.1 mg) as a colorless oil.

实施例 3抑制拓朴 II的抗癌剂和新合成化合物的作用机理的比较 Example 3 Comparison of Mechanisms of Inhibition of Topote II Anticancer Agents and Newly Synthetic Compounds

实施例 4特异性抑制细胞繁殖和抑制机理

Example 4 specifically inhibits cell proliferation and inhibition mechanism

基本为 S期和 M期的反复

特异性抑制繁殖抑制拓朴 IIBasically repeats for S and M phases

Specific inhibition of reproduction inhibition topology II

1)甘遂宁 B ( kansuininB ) ： 3T3细胞 G1，G2期导入 -1) Gansuin B ( kansuininB ) : 3T3 cells G1, G2 phase introduction -

2 ) 巨大戟二萜醇（ Ingenol ) (Z)： MMT细胞 G1,G2期导入 ++2) Ingenol (Z): MMT cells G1, G2 phase import ++

3 ) 巨大戟二萜醇（Ingenol ) (E) 无抑制染色体的凝结（分离） + 实施例 5: 化合物的构造 3) Ingenol (E) No inhibition of chromosome condensation (separation) + Example 5: Construction of a compound

上述化合物 1 - 12的名称分别为：

The names of the above compounds 1 - 12 are:

20- 2Έ，4Έ-癸二烯酯）巨大戟二萜醇（1)* 20- 2Έ，4'Ζ-癸二浠酯）巨大戟二萜醇（2)*: 3-0(2Έ，4'Ζ-癸二烯酯）巨大戟二萜醇（3)， -6 2Έ，4Έ -癸二烯酯）巨大戟二萜醇（4)*，20- 2Έ,4Έ-decadienyl ester) Ingenol (1)* 20- 2Έ, 4'Ζ-癸didecyl ester) Ingenol (2)*: 3-0 (2Έ, 4 'Ζ-decadienyl ester' is a large amount of decyl alcohol (3), -6 2Έ,4Έ-nonadienyl ester) Ingenol (4)*,

- 2Έ，4'Ζ -癸二烯酯) -5-0乙酰基巨大戟二萜醇 (5)*，-0(2Έ，4'Ζ -癸二浠酯) - 20- Ο乙酰基巨大戟二萜醇 (6)，-6 2Έ，4Έ-癸二烯酯)- 20- Ο乙酰基巨大戟二萜醇 (7)*0-Ο癸二烯酯巨大戟二萜醇（8)，- 2Έ, 4'Ζ-decadienyl ester) -5-0 acetyl mega decyl alcohol (5)*, -0 (2 Έ, 4' Ζ - 癸浠 )) - 20- Ο acetyl 戟 huge 戟Dihydric alcohol (6), -6 2 Έ, 4 Έ-decadienyl ester) - 20- Ο acetyl 戟戟萜 ( (7) * 0 - decadienyl ester 戟戟萜 ( (8),

-0(2Έ,4Έ-癸二浠酯）巨大戟二萜醇 (9)*，-0 (2Έ,4Έ-癸浠 ) ester) 戟戟萜 ( (9)*,

-0苯甲酰基- 20-脱氧巨大戟二萜醇 (10)，-0 benzoyl-20-deoxy indanol (10),

- 0·苯甲酰基- 20-脱氧巨大戟二萜醇 1 (11)，- 0·benzoyl-20-deoxy indanol 1 (11),

- 6 2Έ,4Έ-癸二烯酯)- 20 -脱氧巨大戟二萜醇 (12)* - 6 2Έ,4Έ-decadienyl)-20-deoxy-indanol (12)*

n n

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PP WL ΡΡ 09'Ζ, ； ε PP WL ΡΡ 09'Ζ, ; ε

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SAO'I S90'I SWI 91SAO'I S90'I SWI 91

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6 L S f τ I H 6 L S f τ I H

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OT9000/SOOZN3/X3d .689ΐΐ/900ί OAV 物 1，2，4，5，7，9的 ¹³C NMR数据 (125 MHz, CDC1₃ , TMS ) OT9000/SOOZN3/X3d .689ΐΐ/900ί OAV ¹³ C NMR data for 1, 2, 4, 5, 7, ⁹ (125 MHz, CDC1 ₃ , TMS)

醋 Vinegar

酸 1 Acid 1

盐- 1 Salt - 1

22.5 22.5 22.5 22.5 22.5 22.5 22.5 22.5 22.5 22.5

14.0 14.0 14.0 14.0 14.0 14.0 14.0 14.0 14.0 14.0

171.5 171.0 171.5 171.0

20.9 21.1 20.9 21.1

表 3、化合物 12的 NMR数据 [300 MHz, CDC1₃, TMS], ¹³C NMR 数据 [75 MHz, CDCI3 , TMS ] Table 3, NMR data for compound 12 [300 MHz, CDC1 ₃ , TMS], ¹³ C NMR data [75 MHz, CDCI3, TMS]

数值可以互换. 表 4

Values can be interchanged. Table 4

to 50g/ml lOg/ml 2g/ml 0.5 /ml 0.1g/ml To 50g/ml lOg/ml 2g/ml 0.5 /ml 0.1g/ml

Inh. Gro. Inh. Gro. Inh. Gro. Inh. Gro. Inh. Gro. Inh. Gro. Inh. Gro. Inh. Gro. Inh. Gro. Inh. Gro.

CO CO

假白榄酮型（二O萜） False ketone ketone type (20 萜)

1 - 7 - lib 245 45 113 173 99 291 1 - 7 - lib 245 45 113 173 99 291

巨大戟二萜醇 ( Ingenol ) (二萜） Ingenol (European)

G-1- 7-19-2- 2(0)) 240 14 151 11 64 4 102 32 29 85 + G-1- 7-19-2- 2(0)) 240 14 151 11 64 4 102 32 29 85 +

G- 1- 7- 19- 2- 1(②） 206 12 164 7 59 5 104 23 40 74 +G- 1- 7- 19- 2- 1(2) 206 12 164 7 59 5 104 23 40 74 +

G - 1- 7-21- C- 1(③） 215 8 168 4 63 1 142 15 41 86G - 1- 7-21- C- 1 (3) 215 8 168 4 63 1 142 15 41 86

G-l-7- 21-D- 1(④） 232 12 149 12 56 6 106 17 41 101G-l-7- 21-D- 1(4) 232 12 149 12 56 6 106 17 41 101

G-1- 7-22- 2-1(⑤） 78 0 82 12 12 57 - - - 一 +G-1- 7-22- 2-1(5) 78 0 82 12 12 57 - - - One +

G-1- 7- 22- 1- 2(⑥） 91 1 61 21 24 59 - - 一 - +G-1- 7- 22- 1- 2(6) 91 1 61 21 24 59 - - one - +

G- 1-7-22-1- 3(⑦） 85 0 81 14 13 53 - - - 一 +G- 1-7-22-1- 3(7) 85 0 81 14 13 53 - - - One +

G-1- 7- 2 A-4- 1(⑧） 182 10 161 4 48 10 98 25 26 9 +G-1- 7- 2 A-4- 1(8) 182 10 161 4 48 10 98 25 26 9 +

G-l-7-17-2-4((D) 95 1 57 41 87 15 66 21 21 58 +G-l-7-17-2-4((D) 95 1 57 41 87 15 66 21 21 58 +

G-1-6-8-AB - 1(⑩） 96 0 124 0 82 23 75 18 32 82G-1-6-8-AB - 1(10) 96 0 124 0 82 23 75 18 32 82

G-l-6-llAb( ) 99 0 99 0 58 38 68 32 19 69G-l-6-llAb( ) 99 0 99 0 58 38 68 32 19 69

G-l-6-29-A-2-l(s) 59 18 71 63 48 60 78 11 - - + 大戟烷 ( euphane ) (三萜） G-l-6-29-A-2-l(s) 59 18 71 63 48 60 78 11 - - + euphane (three 萜)

69 19 89 27 22 57 - - - - 69 19 89 27 22 57 - - - -

82 0 97 14 24 49 - - 一 - 甘遂烷（ tirucallane ) (三萜） 82 0 97 14 24 49 - - one - ganthane (tirucallane) (three 萜)

1 - 6 - 26 - 3 - 2 - 1 92 2 63 36 11 83 - - - + 1 - 6 - 26 - 3 - 2 - 1 92 2 63 36 11 83 - - - +

实施例 6: 制备药物剂型 Example 6: Preparation of a pharmaceutical dosage form

本发明的化合物可以通过口服、非口服以及皮下注射等手段使用。成年人每人每天的用量为每 1kg体重对应 O.lmg— lOOmg剂量。 The compounds of the present invention can be used by oral, parenteral, and subcutaneous injection. The daily dose per adult is 0.1 mg to 100 mg per 1 kg body weight.

本发明的化合物可以用各种药剂形式使用。比如，片剂、散剂、颗粒、胶嚢、注射剂、栓剂、软膏剂、巴布剂等。在将本发明的化合物制成以上各种剂形的时候，可以按照正常的方法使用制药时常用的载体或是添加物，比如溶剂、基剂、稀释剂、填充基等塑型剂、助溶剂、乳化剂、分散剂、崩解剂、可融化剂、增粘剂、润滑剂等辅助剂、抗氧化剂、防腐剂、芳香剂、甜味剂等添加剂而制成药剂。 The compounds of the invention may be used in a variety of pharmaceutical forms. For example, tablets, powders, granules, capsules, injections, suppositories, ointments, cataplasms, and the like. When the compound of the present invention is formed into the above various dosage forms, a carrier or an additive which is commonly used in pharmaceuticals, such as a solvent, a base, a diluent, a filler, and the like, a cosolvent can be used according to a normal method. An agent such as an emulsifier, a dispersing agent, a disintegrating agent, a meltable agent, a thickener, a lubricant, and the like, an antioxidant, a preservative, a fragrance, a sweetener, and the like.

当本发明提供的化合物或其药学上可接受的盐、对映体、外消旋体、互变异构体或生理官能衍生物单独给药时，优选以药用制剂提供，该制剂包括本发明提供的化合物或其药学上可接受的盐、对映体、外消旋体、互变异构体或生理官能衍生物其药学上可接受的载体或赋形剂以及可任选的一种或多种其它的治疗成份。 When the compound provided by the present invention, or a pharmaceutically acceptable salt, enantiomer, racemate, tautomer or physiological functional derivative thereof, is administered alone, it is preferably provided in a pharmaceutical preparation, the preparation including the present A pharmaceutically acceptable carrier or excipient of the compound or a pharmaceutically acceptable salt, enantiomer, racemate, tautomer or physiologically functional derivative thereof, and optionally one Or a variety of other therapeutic ingredients.

所述制剂包括口服给药制剂、吸入制剂（包括由不同剂量的加压气雾器、喷雾器、吹入器中产生的微粒粉剂或雾剂）、局部给药制剂（包括皮肤给药、口腔给药、舌下给药、眼内给药）。最适合的给药途径取决于用药患者的状况和疾病。制剂通常以单位剂型提供，并且可以通过药学领域中已知的任何方法进行制备。所有的方法都包括将活性成份与载体混合的步骤，载体由一个或多个辅助成分构成。通常情况下通过使活性成分与液体或精细固体载体或两者均匀紧密结合，随后根据需要将所述产物制成制剂；适宜口月良给药的本发明制剂可以以独立的单位如胶嚢剂、扁嚢剂或片剂提供，而每单位含有预定量的活性成分；散剂或颗粒剂；水溶性液体或悬浮液；或水包油型乳剂或油包水型乳剂；也可以是大丸剂、药糖剂或糊剂。 The preparation includes an orally administered preparation, an inhalation preparation (including a particulate aerosol or an aerosol produced by a different dose of a pressurized aerosol device, a nebulizer, an insufflator), a topical preparation (including skin administration, oral administration). Medicine, sublingual administration, intraocular administration). The most suitable route of administration depends on the condition and disease of the patient being administered. The formulations are usually provided in unit dosage form and may be prepared by any methods known in the art of pharmacy. All methods include the step of mixing the active ingredient with a carrier which is comprised of one or more accessory ingredients. Usually, the active ingredient is uniformly and tightly bound to a liquid or a fine solid carrier or both, and then the product is formulated as needed; the preparation of the invention suitable for oral administration can be in a separate unit such as a capsule. , A sputum or tablet is provided, and each unit contains a predetermined amount of the active ingredient; a powder or granule; a water-soluble liquid or suspension; or an oil-in-water emulsion or a water-in-oil emulsion; or a granule or a medicine Sugar or paste.

通过任选与一种或多种辅助成分一起压片或塑型可以制备片剂；通过在适当的机器上压制自由流动形式如粉末或颗粒（任选与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂混合）中的活性馏分可以制备压制片剂；所述片剂可任选为包衣或压痕的，并且配成制剂以提供活性成分的緩释或控释。 Tablets may be prepared by tableting or molding, optionally with one or more accessory ingredients; by compressing free-flowing forms such as powders or granules on a suitable machine (optional with binders, lubricants, inert diluents) The active fraction in the mixture of surfactants or dispersing agents can be used to prepare compressed tablets; the tablets can optionally be coated or indented and formulated to provide sustained or controlled release of the active ingredient.

用于口腔的局部给药的制剂（如口腔含化剂或舌下给药剂），包括在调味基质（如蔗糖、 ***糖）中的活性成份的锭剂。 Formulations for topical administration to the oral cavity (e.g., buccal or sublingual agents), including lozenges of the active ingredient in a flavoring base such as sucrose, arabinose.

可以理解，除上面特别提到的成分外，本发明的制剂还包括本领域相关制剂类型的其它常规成分。下面以化合物（1 )为例列举的实施例，同样适用于本发明中的其它化合物。 It will be understood that in addition to the ingredients specifically mentioned above, the formulations of the present invention also include other conventional ingredients of the type of formulation in the art. The following examples exemplified by the compound (1) are equally applicable to the other compounds in the present invention.

① 550 mg的化合物（1 )、 10550 mg的乳糖、 4500 mg的淀粉均匀混合，添加羟基丙基纤维素溶液 0.15 ml, 炼合制造软块，利用造粒机制造颗粒，进行干燥。干燥后的颗粒中加入 300 mg的硬脂酸镁均匀混合后，利用压片机制造片剂。 1 550 mg of the compound (1), 10550 mg of lactose, and 4500 mg of starch were uniformly mixed, 0.15 ml of a hydroxypropylcellulose solution was added, and a soft block was produced by refining, and pellets were produced by a granulator and dried. After the dried granules were uniformly mixed with 300 mg of magnesium stearate, tablets were produced by a tableting machine.

②将从甘遂提取的化合物 ( 1 ) 10 g与玉米淀粉 40 g混合，加水制成软材，过 12 目筛造粒、干燥，得到颗粒剂，在本颗粒剂中每 500mg 中含化合物（1 ) 100 mg。 2 10 g of the compound ( 1 ) extracted from the sorghum is mixed with 40 g of corn starch, added with water to make a soft material, granulated by a 12-mesh sieve, and dried to obtain granules, and the compound is contained in the granules per 500 mg ( 1) 100 mg.

③将从甘遂提取的化合物（1 ) 40 g与乳糖 100 g、硬脂酸镁 10 g 混合，以每 600 mg填充肠溶胶嚢，本肠溶胶嚢剂中，每个胶嚢含化合物（ 1 ) 160 mg。 3 Compound (1) 40 g extracted from licorice is mixed with 100 g of lactose and 10 g of magnesium stearate to fill the intestinal sol with 600 mg of each of the intestinal sol elixirs. (1) 160 mg.

④将从甘遂提取的化合物（1 ) 25g以普通的注射剂制造法，用加热至 60摄氏度的注射用蒸馏水 1000 ml溶解，用 NaCl调解等张，封入安剖瓶。本注射液 10 ml中含有化合物（1 ) 250 mg。 4 25 g of the compound (1) to be extracted from the sorghum was dissolved in 1000 ml of distilled water for injection heated to 60 ° C by an ordinary injection preparation method, and the isotonic sheets were adjusted with NaCl, and the ampoules were sealed. This injection contains 10 ml of compound (1) 250 mg.

Claims

权利要求 Rights request

1. 以下通式（ I ) 中所表示的二萜类化合物: 1. Diterpenoids represented by the following formula (I):

R3OH2C (I) R3OH2C (I)

式中 Ri至 R₃可以相同或不同，表示氢原子、直链或含支链的饱和或不饱和的取代或未取代的脂肪族基；或表示由通式 RCO -表示的基，其中， R表示直链或含支链的饱和或不饱和的取代或未取代脂肪族基，或者取代或未取代的芳基或杂芳基。 Wherein Ri to R ₃ may be the same or different and represent a hydrogen atom, a straight chain or a branched or saturated or unsaturated substituted or unsubstituted aliphatic group; or a group represented by the formula RCO -, wherein R A linear or branched, saturated or unsaturated, substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl or heteroaryl group.

2、根据权利要求 1所述的二萜类化合物，其特征在于 R RFH,!^

2. A diterpenoid according to claim 1, characterized in that R RFH, !^

3、根据权利要求 1所述的二萜类化合物，其特征在于 1^，1 ₂=11,1 ₃ =CO- (CH=CH)"CH₂)₄ - CH₃( 3. A diterpenoid according to claim 1, characterized in that 1^,1 ₂ =11,1 ₃ =CO- (CH=CH)"CH ₂ ) ₄ - CH ₃ (

4、根据权利要求 1所述的二萜类化合物，其特征在于 RFCO- (CH

4. The diterpenoid according to claim 1, characterized in that RFCO- (CH)

5、根据权利要求 1所述的二萜类化合物，其特征在于 RFCO- (CH =CH)₂- (CH2)4-C¾( ， R₂,R₃=H。 5. The diterpenoid according to claim 1, characterized in that RFCO-(CH=CH) ₂ - (CH2)4-C3⁄4 (, R ₂ , R ₃ = H.

6、根据权利要求 1所述的二萜类化合物，其特征在于

6. The diterpenoid compound according to claim 1, characterized in that

=CH)₂- (CH₂)₄- CH₃C£¾¾R₂=COCH₃,R₃=H。 =CH) ₂ - (CH ₂ ) ₄ - CH ₃ C£3⁄43⁄4R ₂ =COCH ₃ , R ₃ =H.

7、根据权利要求 1所述的二萜类化合物，其特征在于 RFCO- (CH =CH)2-(CH2)4-CH3(^R₂=H,R3=COCH3o 7. A diterpenoid according to claim 1, characterized in that RFCO-(CH=CH)2-(CH2)4-CH3(^R ₂ =H, R3=COCH3o

8、根据权利要求 1所述的二萜类化合物，其特征在于 RFCO- (CH

8. The diterpenoid according to claim 1, characterized in that RFCO- (CH)

9、根据权利要求 1所述的二萜类化合物，其特征在于 Ri， =H,¾ =CO-(CH₂)₈- CH₃。 9. The diterpenoid according to claim 1, characterized in that Ri, =H, 3⁄4 = CO-(CH ₂ ) ₈ - CH ₃ .

10、根据权利要求 1所述的二萜类化合物，其特征在于

10. A diterpenoid according to claim 1 wherein

0- (CH=CH)₂- (CH₂)4- ΟΗ₃( ¾Ι ₃=Η。 0- (CH=CH) ₂ - (CH ₂ )4- ΟΗ ₃ ( 3⁄4Ι ₃ =Η.

11、以下通式（ II ) 中所表示的二萜类化合物： 11. Diterpenoids represented by the following formula (II):

其特征在于式中

酰基或 H，

Characterized by

Acyl or H,

12、根据权利要求 2 - 11中任一项所述的化合物，其特征在于上述化合物为拓朴异构酶 II抑制剂。 The compound according to any one of claims 2 to 11, wherein the compound is a topoisomerase II inhibitor.

13、根据权利要求 2 - 11中任一项所述的化合物，其特征在于上述化合物为仅具有抑制拓朴异构酶 II活性而不具有细胞凋亡活性的拓朴异构酶 II抑制剂。 The compound according to any one of claims 2 to 11, wherein the compound is a topoisomerase II inhibitor having only an inhibitory activity of topoisomerase II and having no apoptotic activity.

14、根据权利要求 2 - 11中任一项所述的化合物，其特征在于在制备治疗与拓朴异构酶 II活性有关的疾病的药物中的用途。 14. A compound according to any one of claims 2 to 11 for use in the manufacture of a medicament for the treatment of a disease associated with topoisomerase II activity.

15、根据权利要求 2 - 11中任一项所述的化合物，其特征在于在制备通过抑制拓朴异构酶 II活性而治疗疾病的药物中的用途。 The compound according to any one of claims 2 to 11, which is useful in the preparation of a medicament for treating a disease by inhibiting the activity of topoisomerase II.

16、根据权利要求 2 - 11中任一项所述的化合物，其特征在于在制备通过抑制动物细胞繁殖而治疗疾病的药物中的用途。 The compound according to any one of claims 2 to 11, which is for use in the preparation of a medicament for treating a disease by inhibiting the proliferation of animal cells.

17、根据权利要求 2 - 11中任一项所述的化合物，其特征在于在制备***疾病的药物中的用途。 17. A compound according to any one of claims 2-11, characterized by the use in the manufacture of a medicament for the treatment of neoplastic diseases.

18、根据权利要求 17所述的化合物，其特征在于所述的肿瘤为实体瘤。 18. A compound according to claim 17 wherein the tumor is a solid tumor.

19、根据权利要求 17所述的化合物，其特征在于所述的肿瘤为乳腺癌。 19. A compound according to claim 17 wherein the tumor is breast cancer.

20、根据权利要求 17所述的化合物，其特征在于所述的肿瘤为食道癌。 20. A compound according to claim 17 wherein the tumor is esophageal cancer.

21、一种药物组合物，包括以权利要求 2 - 11任一项中所述的化合物为有效成分和药物可接受的载体和 /或助剂。 A pharmaceutical composition comprising the compound according to any one of claims 2 to 11 as an active ingredient and a pharmaceutically acceptable carrier and/or adjuvant.

22、一种联合制剂盒，其特征在于可以同时、分别或顺序使用非抑制拓朴异构酶活性的抗癌药物和有效成分包括以权利要求 2 - 11任一项中所述的化合物的药物组合物。 A combination preparation kit, characterized in that the anticancer drug and the active ingredient which can inhibit the activity of the topoisomerase can be used simultaneously, separately or sequentially, and the pharmaceutical composition comprising the compound according to any one of claims 2 to 11 .

23、一种从甘遂中提取的如权利要求 2 - 11任一项中所述的化合物的盐、对映体、外消旋体、互变异构体或生理官能^"生物。 23. A salt, enantiomer, racemate, tautomer or physiological function of a compound as claimed in any one of claims 2 to 11 which is extracted from the genus Ganzi.

24、根据权利要求 23所述的盐、对映体、外消旋体、互变异构体或生理官能衍生物，其特征在于在制备***疾病药物中的用途。 24. A salt, enantiomer, racemate, tautomer or physiological functional derivative according to claim 23, characterized by the use in the manufacture of a medicament for the treatment of neoplastic diseases.