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WO2008031358A1 - 1,2-dihydroxy-3-methyl-9,10-anthraquinone utile dans la fabrication de médicaments pour traiter les cancers - Google Patents

1,2-dihydroxy-3-methyl-9,10-anthraquinone utile dans la fabrication de médicaments pour traiter les cancers Download PDF

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WO2008031358A1
WO2008031358A1 PCT/CN2007/070650 CN2007070650W WO2008031358A1 WO 2008031358 A1 WO2008031358 A1 WO 2008031358A1 CN 2007070650 W CN2007070650 W CN 2007070650W WO 2008031358 A1 WO2008031358 A1 WO 2008031358A1
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cancer
compound
cancer cells
dihydroxy
methyl
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PCT/CN2007/070650
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French (fr)
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Long Yu
Haoxing Zhang
Qingyu Lang
Lisha Tang
Jia Li
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Fudan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to the field of cell biology, and provides the use of the compound s4 for the preparation of an anticancer drug. Background technique
  • Tumors are diseases that seriously endanger human health.
  • the incidence of cancer has increased in recent years. At present, more than 6 million people worldwide die of cancer every year, and the number of new cases is 8 million. This number is increasing year by year.
  • Malignant tumors commonly known as cancer, are unrestricted and diffuse masses caused by the mutating of organs and tissue cells of the human body. It can destroy the organs and tissues of the human body, consumes limited energy in the body, and damages human life and even causes death.
  • Mitosis is a very important stage in the cell cycle process.
  • the difference between a tumor and a normal cell is unrestricted proliferation, that is, mitosis loses its normal regulation.
  • Most tumors occur because of the instability of the genomic group caused by mitosis.
  • the instability of the genome is also derived from the instability of the chromosome.
  • the instability of the chromosome is a characteristic marker of cancer.
  • Abnormal chromosome segregation, central granule replication and segregation can lead to abnormalities in the number of chromosomes per cell, ie aneuploidy, increased chance of heterozygous deletion, loss of tumor suppressor gene or increased number of proto-oncogenes Disrupts cell life metabolism and signaling, increasing the chance of cancer.
  • Kinase plays an important role in the completion of mitosis and cell cycle regulation, and thus has become a research hotspot in molecular biology.
  • a compound of formula I ie 1,2-dihydroxy-3-methyl-9, 10-oxime, or a pharmaceutically acceptable salt or ester thereof Use in the preparation of anti-cancer compositions such as anti-cancer drugs.
  • the composition is a pharmaceutical composition, a nutraceutical composition or a dietary supplement composition.
  • the medicament is for killing cancer cells or inhibiting the growth of cancer cells.
  • the anticancer drug contains 0.001 to 99% by weight (; preferably 0.01 to 90% by weight;) a compound of the formula I and a pharmaceutically acceptable carrier or excipient.
  • the medicament is also for inhibiting phosphokinase Aurora-B.
  • the anticancer drug is an injection, granule, capsule, solution or tablet.
  • the cancer is selected from the group consisting of liver cancer, colon cancer, gastric cancer, and lung cancer.
  • a method for inhibiting growth of a tumor cell in vitro comprising the steps of: adding a compound 1,2-dihydroxy-3-methyl-9, 10- in a culture system of the tumor cell Hey.
  • the tumor cells are selected from the group consisting of liver cancer cells, colon cancer cells, gastric cancer cells, and lung cancer cells.
  • a method of treating cancer comprising the steps of: administering 1,2-dihydroxy-3-methyl-9, 10-oxime or a pharmaceutically thereof to a mammalian subject in need of treatment Acceptable salt.
  • the application amount is from 0.1 mg/kg to 20 mg/kg of body weight per day.
  • Figure 1 is a graph showing the inhibition results of s4 against SW 620 cells. It can be seen that the IC50 (half lethal) of the s4 of the present invention against the human colon cancer cell line (sw620) is about 1 ⁇ . detailed description
  • the present invention provides the use of the compound represented by the following formula (I) in the preparation of an anticancer drug
  • the compound has the name 1,2-dihydroxy-3-methylanthra-9, 10- qui e [ 1 2-dihydroxy-3-methyl-9 10-oxime], abbreviated as s4, and has a molecular weight of 254. It is prepared by a commercially available or conventional method.
  • the invention also includes compounds obtained by conventional substitution of the compounds.
  • the s4 compound of the present invention can be used in the form of a salt or ester derived from a pharmaceutically or physiologically acceptable acid or base.
  • These salts include, but are not limited to, salts or esters formed with: hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, succinic acid, oxalic acid, fumaric acid, Maleic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or isethionic acid.
  • the salts of halides are also suitable.
  • salts include: salts with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, as well as esters, carbamates or other conventional "prodrugs" (when given in this form) In the case of medicine, it can be converted into an active part in the body).
  • the compound s4 can be used for the preparation of an anticancer drug.
  • the present invention detects the action of the compound s4 on tumor cells and cancer cells according to a standard MTS assay, and the results show that the s4 of the present invention is applicable to various tumor cells and cancer cells, such as liver cancer cells, colon cancer cells, gastric cancer cells, lung cancer cells, and the like. , have a killing or inhibition effect.
  • the compound s4 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This further confirmed that the compound s4 of the present invention has an effect of inhibiting malignant tumors.
  • AIK Alzheimer's disease kinase
  • Aikl Aik2 Aurora-B
  • Aik3 Aik3 mainly plays a role in the mitosis of cells.
  • Aik2 acts as a chromosomal concomitant protein involved in the regulation of the interaction between the centromere and the spindle microtubule.
  • Aik2 migrates from the centromere to the middle zone of the cell, and is distributed at the end of the cell plate and the posterior mitotic bridge. Post-mitotic event, so staining
  • the separation of the body is related to cytokinesis. Mutations in Aik2 inhibit the formation of dividing sulcus and lead to the formation of multinucleated cells.
  • Aik2 is localized to 17ql3, an area that is abnormal in a variety of human cancer cells, and Aik2 is highly expressed in abnormally ploidy colon cancer cell lines. Therefore, researchers are looking for molecules that interact with Aik2 and use them as antitumor drugs.
  • the present invention also establishes a mouse model of transplanted tumor for detecting the effect of s4 on tumors and cancer cells in vivo. The results also show that s4 can inhibit tumor growth in vivo.
  • the anticancer drug prepared from the compound s4 is a pharmaceutical composition comprising a therapeutically effective amount of the compound s4 and a pharmaceutically acceptable carrier or excipient.
  • the effective application amount is 0.1 mg / kg to 20 mg / kg body weight per day.
  • the antitumor drug prepared may be an injection or a tablet or the like.
  • the present invention can provide different effects when administered (administered) therapeutically.
  • these materials can be formulated in a non-toxic, inert, and pharmaceutically acceptable aqueous carrier medium wherein the pH is usually from about 5 to about 8, preferably from about 6 to about 8, although the pH may be The nature of the formulation and the condition to be treated vary.
  • the formulated pharmaceutical compositions can be administered by conventional routes including, but not limited to, intramuscular, intraperitoneal, subcutaneous, intradermal, intratumoral, or topical administration.
  • s4 of the present invention can be used in combination with a suitable pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carrier include, but are not limited to, saline, buffer, dextrose, water, glycerol, ethanol, and combinations thereof.
  • the pharmaceutical preparation should be matched to the mode of administration.
  • the s4 of the present invention can be prepared in the form of an injection, for example, by a conventional method using physiological saline or an aqueous solution containing glucose and other adjuvants.
  • Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods.
  • compositions such as injections, solutions, tablets and capsules are preferably prepared under sterile conditions.
  • the active ingredient is administered in a therapeutically effective amount, for example, from about 1 microgram per kilogram body weight to about 5 milligrams per kilogram body weight per day.
  • s4 of the invention may also be used with other therapeutic agents.
  • a therapeutically effective amount of s4 can be administered to a mammal, wherein the therapeutically effective dose is typically at least about 10 micrograms per kilogram of body weight, and in most cases no more than about 80 milligrams per kilogram.
  • the body weight preferably the dose is from about 500 micrograms per kilogram of body weight to about 2 milligrams per kilogram of body weight.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician. Cancer has become the first cause of death, and the substances that kill tumors and cancer cells have become the research hotspots in the biomedical field.
  • the s4 of the present invention has a killing or inhibiting effect on various tumor cells and cancer cells; meanwhile, the compound s4 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This all proves that the compound s4 of the present invention has an effect of inhibiting malignant tumors.
  • the compound s4 of the present invention can be used in combination with a suitable pharmaceutically acceptable carrier to prepare an anticancer drug to inhibit the continued growth of the tumor.
  • the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the human Aurora-B protein kinase (NCBI accession number NP-004208) was cloned, expressed and purified using E. coli expression system for high-throughput screening experiments.
  • AURORAB phosphorylation substrate MBP (UPSTATE, CAT#13-110, lot#27845), covalently binds ⁇ - 33 [ on the [ ⁇ - 33 ⁇ ]- ⁇ in solution to the substrate. Its Ser is phosphorylated to produce the substrate 33 P-MBP with isotopic labeling.
  • the activity of the enzyme was detected by counting the scintillation liquid by counting with a liquid scintillation counter, and the inhibition of the activity of the different compounds was observed to initially evaluate the activity of the compound.
  • the IC50 is 632nM.
  • Seed plate 1000 cells / hole
  • Cell line human colon cancer cell line (sw620)
  • the pharmaceutical composition in the form of a tablet is prepared by a conventional technique by mixing the following components and then directly compressing the tablet, and the formulation is as follows:

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Description

1，2-籽基 -3-甲基 -9，10-蒽醌在制备抗癌药物中的应用 技术领域
本发明涉及细胞生物学领域， 提供了化合物 s4在制备抗癌药物中的应用。 背景技术
肿瘤是严重危害人类健康的疾病。 近年来肿瘤的发病率日见增长， 目前全世界 每年有 600多万人死于癌症， 新发病例 800万， 这数字还在逐年增加。 我国 13亿人 口中每年有百万新发癌症病人， 待治疗病人约 200万， 死亡约 130万。 预计到 2006 年年底， 我国将有 170万人死于癌症， 癌症已成为第一位死因。
恶性肿瘤俗称癌症，是人体的器官和组织细胞发生变异后引起的无限制生长的 和扩散的肿块。 它可以破坏人体的器官和组织功能， 消耗体内有限能量， 而使人的生 命活动受到损害， 甚至导致死亡。
有丝分裂是细胞周期过程中很重要的一个阶段。肿瘤与正常细胞的区别就是无 限制增生， 即有丝分裂失去正常调控。 大多数的肿瘤其发生原因是有丝分裂所致的基 因组的不稳定性， 基因组的不稳定又来源于染色体的不稳定， 染色体的不稳定是癌症 的特征性标志。 染色体的分离、 中心粒的复制和分离发生异常， 会导致每个细胞染色 体数目的异常， 即非整倍体， 增加杂合性缺失的机会， 抑癌基因的缺失或原癌基因的 数目增加都会使细胞生命代谢和信号传导发生紊乱， 增加癌变的机会。激酶在完成有 丝分裂和细胞周期调控中起着重要作用， 从而成为目前分子生物学的研究热点。
为了治疗肿瘤， 本领域迫切需要开发能够有效抑制肿瘤细胞生长的化合物。 发明内容
本发明的目的是提供化合物 s4在制备抗癌药物中的应用。 在本发明的第一方面，提供了一种式 I所示的化合物， 即 1,2-二羟基 -3-甲基 -9, 10- 蒽醌， 或其药学上可接受的盐或酯在制备抗癌的组合物 （如抗癌药物） 中的应用。
Figure imgf000003_0001
在另一优选例中， 所述的组合物为药物组合物， 保健品组合物或饮食补充剂组合 物。
在另一优选例中， 所述的药物用于杀伤癌细胞或抑制癌细胞的生长。
在另一优选例中， 所述的抗癌药物含有 0.001-99wt% (；较佳地 0.01-90wt%；)式 I 化合物和药学上的载体或者赋形剂。
在另一优选例中， 所述的药物还用于抑制磷酸激酶 Aurora-B。
在另一优选例中， 该抗癌药物是针剂、 颗粒剂、 胶囊、 溶液或片剂。
在另一优选例中， 所述的癌症选自： 肝癌、 结肠癌、 胃癌和肺癌。
在本发明的第二方面， 提供了一种体外抑制肿瘤细胞生长的方法， 包括步骤： 在所述肿瘤细胞的培养体系中添加化合物 1,2-二羟基 -3-甲基 -9, 10-蒽醌。
在另一优选例中， 所述的肿瘤细胞选自： 肝癌细胞、 结肠癌细胞、 胃癌细胞和 肺癌细胞。
在本发明的第三方面， 提供了一种治疗癌症的方法， 包括步骤： 给需要治疗 的哺乳动物对象施用 1,2-二羟基 -3-甲基 -9, 10-蒽醌或其药学上可接受的盐。
在另一优选例中， 所述的施用量为每天 0. 1毫克 /千克至 20毫克 /千克体重。 附图说明
图 1为 s4对 SW620细胞抑制结果图。 可见， 本发明的 s4对人类结肠癌细胞株 ( sw620 ) 的 IC50 (半数致死）为约 1 μ Μ。 具体实施方式
本发明提供了结构如下式 (I)所示的所示的化合物在制备抗癌药物中的应用
Figure imgf000004_0001
所述化合物的名称为 1 , 2-dihydroxy-3-methylanthra-9, 10- qui e [ 1 2-二羟基 -3-甲基 -9 10-蒽醌]， 简称为 s4， 分子量为 254， 可通过市售获得或常规方法制备。 本发明还包括对该化合物进行常规替代所得到的化合物。
本发明的 s4化合物可以以由药学上或生理学可接受的酸或碱衍生的盐或酯 形式使用。 这些盐包括（但不限于）与如下酸形成的盐或酯： 氢氯酸、 氢溴酸、硫酸、 柠檬酸、 酒石酸、 磷酸、 乳酸、 丙酮酸、 乙酸、 琥珀酸、 草酸、 富马酸、 马来酸、 草酰乙酸、 甲磺酸、 乙磺酸、 苯磺酸、 或羟乙磺酸。 卤化物的盐同样适用。 其他盐 包括： 与碱金属或碱土金属（如钠、 钾、 钙或镁）形成的盐， 以及以酯、 氨基甲酸酯 或其他常规的 "前体药物" 的形式（当以这种形式给药时， 在体内可转化成活性部 分）。 本发明中， 化合物 s4可用于制备抗癌药物。
本发明按标准 MTS实验检测了化合物 s4对于肿瘤细胞和癌细胞的作用情况， 结果显示， 本发明的 s4对多种肿瘤细胞和癌细胞， 例如肝癌细胞、 结肠癌细胞、 胃 癌细胞和肺癌细胞等， 都有杀伤或者抑制效果。
进一步研究显示， 本发明的化合物 s4对磷酸激酶 Aurora-B 有抑制作用。 这进一步证实了本发明的化合物 s4具有抑制恶性肿瘤的作用。
恶性肿瘤俗称癌症， 是人体的器官和组织细胞发生变异后引起的无限制生长 的和扩散的肿块。 激酶在完成有丝分裂和细胞周期调控中起着重要作用， 从而成为 目前分子生物学的研究热点。 AIK (Aur0ra/Ipl l Kinase )是目前已知的五大调节性激 酶家族之一。 到目前为止， 人类 Aiks家族共发现三个成员： Aikl Aik2 (Aurora-B) 和 Aik3。 其中， Aik2主要在细胞有丝分裂期起作用。 它作为染色体伴随蛋白参与调 节着丝粒与纺锤体微管的相互作用， 在中期至后期这一瞬时， Aik2 由着丝粒迁移至 细胞中间区带， 末期分布于细胞盘和后有丝分裂桥， 参与后有丝分裂事件， 故与染色 体的分离和胞质分裂有关。 Aik2 的突变使分裂沟的形成被抑制， 并导致形成多核细 胞。 Aik2定位于 17ql3， 这一区域在人类多种癌细胞中出现异常， 而在异常倍性的结 肠癌细胞株中 Aik2高表达。 因此， 科研人员纷纷寻找与 Aik2作用的分子， 并将其作 为抗肿瘤药物来研究。
本发明还建立了移植瘤小鼠模型， 用于检测 s4对体内肿瘤和癌细胞的作用。 结果也显示 s4可以抑制体内肿瘤生长。 本发明中， 由化合物 s4制备的抗癌药物是由含有效治疗量的化合物 s4和药 学上的载体或者赋形剂组成的药物组合物。
本发明中， 所述的有效应用量为每天 0. 1毫克 /千克至 20毫克 /千克体重。 本发明中， 所制备的抗肿瘤药物可以是针剂或片剂等。
本发明 s4及其类似物等， 当在治疗上进行施用（给药）时， 可提供不同的效 果。 通常， 可将这些物质配制于无毒的、 惰性的和药学上可接受的水性载体介质 中， 其中 pH通常约为 5-8， 较佳地 pH约为 6-8， 尽管 pH值可随被配制物质的性 质以及待治疗的病症而有所变化。 配制好的药物组合物可以通过常规途径进行给 药， 其中包括（但并不限于）： 肌内、 腹膜内、 皮下、 皮内、 瘤内、 或局部给药。
以本发明的 s4为例， 可以将其与合适的药学上可接受的载体联用。这类药 物组合物含有治疗有效量的化合物和药学上可接受的载体或赋形剂。 这类载体包 括（但并不限于）： 盐水、 缓冲液、 葡萄糖、 水、 甘油、 乙醇、 及其组合。 药物制 剂应与给药方式相匹配。本发明的 s4可以被制成针剂形式， 例如用生理盐水或含 有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。 诸如片剂和胶囊之类的药 物组合物， 可通过常规方法进行制备。 药物组合物如针剂、 溶液、 片剂和胶囊宜 在无菌条件下制造。活性成分的给药量是治疗有效量， 例如每天约 1微克 /千克体 重-约 5毫克 /千克体重。 此外， 本发明的 s4还可与其他治疗剂一起使用。
当本发明的 s4被用作药物时， 可将治疗有效剂量的 s4施用于哺乳动物， 其中该治疗有效剂量通常至少约 10微克 /千克体重， 而且在大多数情况下不超过 约 80毫克 /千克体重，较佳地该剂量是约 500微克 /千克体重-约 2毫克 /千克体重。 当然， 具体剂量还应考虑给药途径、 病人健康状况等因素， 这些都是熟练医师技 能范围之内的。 癌症已成为第一位死因，杀伤肿瘤和癌细胞生长的物质也由此成为了目前生物 医药界的研究热点。 本发明的 s4对多种肿瘤细胞和癌细胞都有杀伤或者抑制效果； 同时， 本发明的化合物 s4对磷酸激酶 Aurora-B 有抑制作用。 这都证明了本发明 的化合物 s4具有抑制恶性肿瘤的作用。将本发明的化合物 s4可用于与合适的药学 上可接受的载体联用制备抗癌药物， 以抑制肿瘤继续生长。 下面结合具体实施例， 进一步阐述本发明。 应理解， 这些实施例仅用于说明本 发明而不用于限制本发明的范围。 下列实施例中未注明具体条件的实验方法， 通常按 照常规条件如 Sambrook等人， 分子克隆：实验室手册（New York : Cold Spring Harbor Laboratory Press, 1989)中所述的条件， 或按照制造厂商所建议的条件。 实施例 1 体外酶活抑制实验
应用大肠杆菌表达系统， 克隆、 表达并纯化得到了人源 Aurora-B蛋白激酶 ( NCBI 登陆号为 NP— 004208 ) ，用于高通量筛选筛选实验。 采用放射性同位素技 术， AURORAB磷酸化底物 MBP ( UPSTATE公司， CAT#13- 110， lot#27845 ) ，将溶液 中 [γ-33Ρ] -ΑΤΡ上的 γ-33Ρ转移共价结合到底物， 使其 Ser磷酸化， 产生具有同位素 标记的底物 33P— MBP。 最后加入闪烁液通过液体闪烁计数仪计数来检测该酶活性， 可以观察不同化合物对其活性的抑制情况， 以初步评价化合物的活性。
平行实验结果显示， 本发明的化合物 s4对 Aurora-B蛋白激酶活性抑制的
IC50为 632nM。 实施例 2癌细胞抑制实验
按照标准 MTS实验进行， 其中具体参数如下：
种板： 1000个细胞 /孔
化合物： s4
培养时间： 96h
加药品后处理时间： 3h
化合物浓度梯度： 单位： uM 重复实验： 6组
数据给出形式： 平均值士标准差
细胞株： 人类结肠癌细胞株 （sw620 )
结果显示， 本发明的化合物 s4对 SW620抑制的 IC50约为 1 μ Μ。 具体见下
Figure imgf000007_0001
实施例 3
药物组合物 （片剂） 的制备
利用常规技术， 混合以下组分， 然后直接压片， 制备片剂形式的药物组合物， 其配方如下：
Figure imgf000007_0002
在本发明提及的所有文献都在本申请中引用作为参考， 就如同每一篇文献被 单独引用作为参考那样。 此外应理解， 在阅读了本发明的上述讲授内容之后， 本 领域技术人员可以对本发明作各种改动或修改， 这些等价形式同样落于本申请所 附权利要求书所限定的范围。

Claims

权 利 要 求
1. 一种式 I所示的化合物 1,2-二羟基 -3-甲基 -9, 10-蒽醌或其药学上可接受的盐或
Figure imgf000008_0001
2. 如权利要求 1所述的应用， 其特征在于， 所述的药物用于杀伤癌细胞或抑制 癌细胞的生长。
3.如权利要求 1所述的应用，其特征在于，所述的抗癌药物含有 0.001-99wt% 式 I化合物和药学上的载体或者赋形剂。
4. 如权利要求 1所述的应用， 其特征在于， 所述的药物还用于抑制磷酸激酶
Aurora-B。
5. 如权利要求 1所述的应用， 其特征在于， 该抗癌药物是针剂、 颗粒剂、 胶 囊、 溶液或片剂。
6. 如权利要求 1所述的应用， 其特征在于， 所述的癌症选自： 肝癌、 结肠癌、 胃癌和肺癌。
7. 一种体外抑制肿瘤细胞生长的方法， 其特征在于， 包括步骤： 在所述肿瘤 细胞的培养体系中添加化合物 1,2-二羟基 -3-甲基 -9, 10-蒽醌。
8.如权利要求 7所述的方法， 其特征在于， 所述的肿瘤细胞选自： 肝癌细胞、 结肠癌细胞、 胃癌细胞和肺癌细胞。
9. 一种治疗癌症的方法， 其特征在于， 包括步骤： 给需要治疗的哺乳动物对 象施用 1,2-二羟基 -3-甲基 -9, 10-蒽醌或其药学上可接受的盐。
10. 如权利要求 9所述方法， 其特征在于， 所述的施用量为每天 0.1毫克 /千 克至 20毫克 /千克体重。
PCT/CN2007/070650 2006-09-07 2007-09-07 1,2-dihydroxy-3-methyl-9,10-anthraquinone utile dans la fabrication de médicaments pour traiter les cancers WO2008031358A1 (fr)

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