WO2012136144A1 - 一类具有抗肿瘤活性的喜树碱衍生物 - Google Patents

一类具有抗肿瘤活性的喜树碱衍生物 Download PDF

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WO2012136144A1
WO2012136144A1 PCT/CN2012/073578 CN2012073578W WO2012136144A1 WO 2012136144 A1 WO2012136144 A1 WO 2012136144A1 CN 2012073578 W CN2012073578 W CN 2012073578W WO 2012136144 A1 WO2012136144 A1 WO 2012136144A1
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branched
linear
camptothecin
cyclic
document
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PCT/CN2012/073578
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English (en)
French (fr)
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雷晓光
张秀国
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Lei Xiaoguang
Zhang Xiuguo
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Priority to JP2014502977A priority Critical patent/JP5755796B2/ja
Priority to RU2013149416/04A priority patent/RU2561118C2/ru
Priority to US14/006,102 priority patent/US9006439B2/en
Priority to KR1020137020846A priority patent/KR101575079B1/ko
Priority to EP12768102.1A priority patent/EP2695884B1/en
Publication of WO2012136144A1 publication Critical patent/WO2012136144A1/zh

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4738Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/475Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • A61K9/2018Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4866Organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

Definitions

  • the present invention relates to antitumor drug compounds, and more particularly to a class of camptothecin derivatives having novel chemical structures and highly potent antitumor activities, and their preparation and use. Background technique
  • Cancer cancer is one of the serious diseases that currently endanger people's lives and health. According to statistics from the World Health Organization (WHO), the annual incidence of cancer in the world is about 16 million, and the death rate is about 6 million. It has become the second only cardiovascular disease. The second killer of civilization. At present, there are more than 70 kinds of anti-tumor drugs listed globally, which are progressing at a rate of 1-2 new drugs per year. However, China is still in the early stage of research and development of anti-tumor drugs. Due to economic and supply reasons, the majority of cancer patients still do not get the most advanced drug treatment. Therefore, the development of innovative anti-tumor drugs with independent intellectual property rights is of great significance to the country's economic construction and health care construction.
  • WHO World Health Organization
  • Camptothecin is an alkaloid isolated from the camphor tree of Campanulaceae. Its target is to inhibit DNA topoisomerase I. Due to the poor selectivity of camptothecin, the production of hematuria and myelosuppression limits the application.
  • the structurally modified semi-synthetic camptothecin derivatives increase selectivity, reduce toxicity, and improve efficacy.
  • camptothecin drugs marketed at home and abroad include irinotecan (CPT-11), topotecan (Topotecan), 10-hydroxycamptothecin and Beirutukang (CKD-602) marketed in 2004.
  • NP-1350 Kernitecin
  • Gimatecan Gimatecan
  • Chimmitecan Chimmitecan.
  • Irinotecan is the most successful camptothecin derivative with structural modification. It has a broad-spectrum anticancer effect. It is a first-line drug for the treatment of metastatic colorectal cancer after 5-fluorouracil for 40 years. It is also used for lung cancer and ovarian cancer. , treatment of breast cancer, stomach cancer and pancreatic cancer. Topotecan is the worst one. Preclinical evaluation is ineffective for most tumors. It is also used only for small cell lung cancer that is most sensitive to chemotherapy in clinical use, and has a short remission time and poor effect. Camptothecin is a 5-ring alkaloid, and various structural modifications can be made at C_7, 9-12, and 20 positions.
  • Structural modification at the C_7 and 9 positions yields highly efficient and low toxicity compounds such as: irinotecan introduces an ethyl group at the C-7 position; and gematecan introduces a (N-tert-butyloxy) group at the C-7.
  • irinotecan introduces an ethyl group at the C-7 position
  • gematecan introduces a (N-tert-butyloxy) group at the C-7.
  • the group is fat-soluble and can pass through the blood-brain barrier
  • gematican is undergoing clinical trials for the treatment of glioma.
  • the introduction of propylene groups at the C-9 position by gimidine has a good antitumor effect.
  • topotecan introduced dimethylaminomethyl at position 9 did not increase the efficacy and toxicity, and increased toxicity compared to 10-H-CPT, but increased water solubility. So can you introduce the corresponding group at 7-9? Improving the activity of a compound is
  • the inventors of the present invention have conducted a very systematic study on camptothecin antitumor drugs, and through long-term experimental screening, it has been found that the introduction of hydrazine or other olefinic compound containing a hetero atom at the C-9 position, while at C-10 or A novel structure-derived compound having a functional group such as a hydroxyl group at the C-11 position [in the present invention] has a good antitumor activity, and has an excellent antitumor effect in vivo, and is currently the best selective.
  • One of the new compounds of camptothecins thus showing the prospect of such compounds in the development of anti-tumor drugs. This type of compound has not been reported at home and abroad, and belongs to the novel structural compound of the invention. Summary of the invention
  • the present invention is: 1. Provided a new class of camptothecin derivatives having antitumor activity, 2. such compounds and their pharmaceutical compositions, and 3. The use of such compounds and preparation combinations in the treatment of tumors.
  • R represents: H; d-. Linear, branched or cyclic alkyl; F substituted d-linear, branched or cyclic alkyl; d-. Linear, branched or cyclic acyl; F-substituted d-Cw straight chain, branched or cyclic acyl; C 6 -C 18 carbon aromatic ring; C 6 _C 18 containing halogen atom (F, Cl, Br, I), nitro (N0 2 ), hydroxy (OH), amino (NH 2 ), cyano (CN) substituent carbon aromatic ring; aromatic ring containing hetero atom (N, 0, S).
  • X represents: 0; NH; NR 6 ; R 6 represents: d-.
  • R 2 represents: H; d-. Linear, branched or cyclic alkyl; F substituted d-Cw straight, branched or cyclic alkyl.
  • R 4 represents: H which is the same or different at the C10 and C11 positions; a halogen atom (F, Cl, Br, I); a nitro group (N0 2 ); a hydroxyl group (OH); an amino group (NH 2 ); d-.
  • a linear, branched or cyclic carbonyl group an F-substituted d-straight chain, a branched or cyclic carbonyl group; a linear, branched or cyclic carbonyl group containing a D atom of a N atom; containing a natural or unnatural amino acid and It consists of a carbonyl group at the C-terminus of the polypeptide.
  • the pharmaceutically acceptable salt of the above compound is characterized in that the (4'-piperidylpiperidine)carbonyloxy group has a basic amino group or a salt of an amino group of a natural or unnatural amino acid with a pharmaceutically acceptable inorganic or organic acid.
  • These salts can make the drug water soluble.
  • Particularly preferred in the present invention are the following compounds (CPT1-CPT10):
  • CPT9 9-tert-Butoxyethylindole-10-[(4'-piperidylpiperidine)carbonyloxy]-20-phenylalaninecarbonyloxy-Hi Lignoline
  • the invention also includes pharmaceutical compositions comprising an effective amount of a compound of the invention.
  • the pharmaceutical composition can be used for oral administration and injection administration.
  • the dosage form for oral administration may be a tablet, a capsule, an oral solution, a granule, a suspension or the like.
  • Oral Dosage Forms The medicinal dressings used are conventional dressings, including diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, bulking agents, and the like.
  • the injection may be an injection, a powder injection, a lyophilized powder, a liposome or the like.
  • the medicinal dressing for injection is a conventional dressing, including a solvent, a diluent, a solubilizer, a pH adjuster, and the like.
  • An effective dose refers to a therapeutically effective dose which exerts a beneficial effect on a patient, and the amount thereof varies depending on the route of administration and the administration scheme.
  • MPT assay was used to detect CPT1-CPT10, irinotecan active (SN-38), gimacitant and topotecan in vitro against A549 (non-small cell lung cancer), HT-29 (colon cancer), OV-3 (ovarian cancer), U87 (glioma), BX-PC3 (pancreatic cancer) cell line inhibition.
  • the results showed that CPT1, CPT4, CPT5, CPT6, CPT9, and CPT10 were prodrugs in CPT1-10 and had no significant activity in vitro (not recorded in the table).
  • CPT2, CPT3, CPT7 and CPT8 have obvious cytotoxicity.
  • CPT2, CPT3, CPT7, CPT8, gematidine, SN_38, and topotecan on the above five cell lines were from strong to weak U87, BX-PC3 HT-29 OV-3, A549.
  • the average concentration (nM) of the above compounds against U87 BX-PC3 HT-29 OV-3, A549 inhibiting 50% cell growth were: CPT7 (3.3), CPT3 (7.1), and gematidine (2. 7), CPT2 (9.1), SN-38 (10. 5), CPT8 (12. 9), Topotecan (19. 7). (see attached Table 1).
  • Example 1 Specific preparation method of CPT1:
  • Example 3 Preparation of tablets containing CPT1
  • Example 5 Preparation of CPT2, CPT3 tablets and capsules
  • the in vitro cytotoxicity was measured by the MTT method, and cells in good condition were taken to prepare a cell suspension.
  • the cell suspension was inoculated into a 96-well plate, 200 ⁇ l of well, and cultured in a constant temperature C 0 2 incubator for 24 hours.
  • the test drug was added, 20 ul / well, and cultured for 48 hours.
  • MT T was added to a 96-well plate, 20 ul / well, and reacted for 4 hours in an incubator.
  • the supernatant was aspirated, DMS0, 20 ul / well was added, and the absorbance of each well was measured by an enzyme-linked immunosorbent at a wavelength of 570 nm. Value, calculate the killing effect on cells.
  • Table 1 Inhibition of tumor cells by new camptothecin derivatives in vitro
  • A549 non-small cell lung cancer
  • HT-29 colon cancer
  • OV-3 ovarian cancer
  • U87 glioma
  • BX-PC3 pancreatic cancer above compounds for U87, BX-PC3, HT-29, OV-3
  • the average concentration (nM) of A549 inhibiting 50% cell growth was: CPT7 (3.3), CPT3 (7.1), Gimatik (2.7), CPT2 (9.1), SN-38 (10 ⁇ 5), CPT8 ( 12.9), Topotecan (19.7).
  • Example 6 Antitumor effect in vivo
  • mice female.
  • Transplantation of tumors Take vigorously growing tumor tissue and cut into fine pieces with sterile scissors, each inoculated with 50 mg of tumor tissue. Treatment begins on days 6-10 after tumor implantation, at which time the tumor weight is around 300 mg. The nude mice were weighed and the tumor volume was measured every other day. Transplanted tumors tested: human breast cancer (MX-1), human non-small cell lung cancer (A549), human ovarian cancer (SK-0V3), human colon cancer (HT29), human pancreatic cancer (BX_PC_3).
  • MX-1 human breast cancer
  • A549 human non-small cell lung cancer
  • SK-0V3 human ovarian cancer
  • HT29 human pancreatic cancer
  • BX_PC_3 human pancreatic cancer
  • tumor inhibition rate (%) (control group tumor volume - treatment group volume) / control group volume X 100%.
  • the dose is the same toxic dose with a 12-15% reduction in body weight determined after the test.
  • TS tumor volume
  • Table 4 Therapeutic effect of human brain glioma U87 brain transplantation tumor

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Abstract

本发明提供一类新的具有抗肿瘤活性喜树碱衍生物(基本结构如图)及该类化合物的组合及其应用。本发明的化合物具有很好的水溶性和稳定性,在本类药物中本发明的化合物选择性好,具有很高的治疗指数。该类化合物在肿瘤的药物治疗中有很好的治疗前景。

Description

说明书
一类具有抗肿瘤活性的喜树碱衍生物
技术领域
本发明涉及抗肿瘤药物化合物, 更具体地, 涉及一类具有新颖化学结构和高效抗 肿瘤活性的喜树碱衍生物和它们的制备及应用。 背景技术
癌症肿瘤是目前危害人民生命和健康的严重疾病之一, 据世界卫生组织 (WHO)统 计资料表明, 全世界癌症每年发病约 1600万人, 死亡约 600万人, 已成为仅次于心血 管病的人类第二杀手。 目前全球上市的抗肿瘤药物总计为七十余种, 以每年 1-2 种新 药问世的速度进展。 然而我国在抗肿瘤药物研制开发方面还处于初期阶段,由于经济 上、 供应上的原因, 广大肿瘤患者还得不到最先进的药物治疗。 因此研制具有自主知 识产权的创新型的抗肿瘤药物对于国家的经济建设和健康医疗建设都具有重大意义。 喜树碱 (Camptothecin, CPT)是从珙桐科植物喜树中分离的生物碱。 其作用靶点是抑制 DNA拓扑异构酶 I。 由于喜树碱选择性差, 产生血尿和骨髓抑制限制了应用。 经结构改 造的半合成喜树碱衍生物提高了选择性, 降低毒性, 提高了疗效。 目前, 国内外上市 的喜树碱类药物有伊立替康(CPT-11 ),拓扑替康(Topotecan ), 10-羟基喜树碱和 2004 年上市的贝鲁替康(CKD-602)。 已进行期临床研究的有 NP-1350 (Karenitecin), 吉马 替康 (Gimatecan) , 吉咪替康 (Chimmitecan) 等。
伊立替康是结构修饰最成功的喜树碱衍生物, 具有广谱的抗癌作用, 是 40年来继 5-氟尿嘧啶以后再次用于治疗转移性结直肠癌一线药物, 也用于肺癌、 卵巢癌、 乳腺 癌、 胃癌和胰腺癌的治疗。 拓扑替康是最差的一个, 临床前评价对大部分肿瘤作用无 效, 在临床使用方面也仅用于对化疗最敏的小细胞肺癌, 而且缓解时间较短, 作用差。 喜树碱是 5环生物碱, 在 C_7、 9-12、 20位均可进行多种结构修饰改造。 在 C_7、 9位上进行结构修饰可获得高效低毒的化合物, 如: 伊立替康在 C-7位引入乙基; 吉 马替康在 C-7引入 (N-叔丁基氧基) 甲基肟, 该基团具有脂溶性, 能透过血脑屏障, 吉马替康正在进行治疗脑胶质瘤的临床试验。 吉咪替康在 C-9位引入丙烯基也有较好 的抗瘤作用。 但是在 9位引入二甲胺基甲基的拓扑替康并没有增加药效和减低毒性, 而且较 10-0H-CPT毒性增加, 只是增加了水溶性。 所以在 7-9位引入相应的基团能否 改善化合物的活性则由引进基团的性质所决定。
Figure imgf000003_0001
本发明的发明人对喜树碱类抗肿瘤药物进行过非常系统的研究,通过长期实验筛 选,发现在 C-9 位上引入肟或其他含杂 N原子的烯烃化合物, 同时在 C-10 或 C-11 位上 引入羟基等官能团的衍生物 [发明内容中结构式(1) ]得到的新结构的化合物具有很好 的抗肿瘤活性,其体内抗肿瘤作用有明显提高,是目前选择性最好的喜树碱类新化合物 之一.从而显示出这类化合物在抗肿瘤药物开发中的前景。该类化合物在国内外还没有 任何报道, 属于发明的新结构化合物。 发明内容
本发明是: 1.提供一类新的具有抗肿瘤活性喜树碱衍生物, 2.该类化合物和它们药物组 合物及 3. 该类化合物和制备组合在治疗肿瘤中的应用。
1.新的喜树碱衍生物基本化学结构如下:
Figure imgf000003_0002
结构式中:
R: 代表: H; d- 。的直链, 支链或环状烷基; F取代的 d- 直链, 支链或环状烷基; d- 。的直链, 支链或环状酰基; F取代的 d-Cw 直链, 支链或环状酰基; C6-C18的碳 芳香环; C6_C18的含有卤原子(F, Cl, Br, I ), 硝基 (N02), 羟基 ( OH), 氨基 (NH2), 氰基 (CN) 取代基的碳芳香环; 含有杂原子 (N, 0, S ) 的芳香环。
X代表: 0; NH; NR6; R6代表: d- 。的直链, 支链或环状烷基; F取代的 d- 直链, 支链或环状烷基; ( 。的直链, 支链或环状酰基; F取代的 d-Cw 直链, 支链或环状 酰基。
R2代表: H; d- 。的直链, 支链或环状烷基; F取代的 d-Cw 直链, 支链或环状烷基。
和 '代表:相同或不同的 H; F; d- 。的直链, 支链或环状烷基; F取代的 d- 。 直 链, 支链或环状烷基。
R4代表:在 C10位和 C11位相同或不同的 H; 卤素原子(F, Cl, Br, I); 硝基(N02); 羟基 (OH); 氨基 (NH2); d- 。的直链, 支链或环状烷基; F取代的 d- 直链, 支链 或环状烷基; d- 。的直链,支链或环状酰基; F取代的 d- 直链,支链或环状酰基; 在 C10位或 C11位的 0R7; R7代表: d- 。的直链, 支链或环状羰基; F取代的 d- 直链, 支链或环状羰基; 含有 N原子的 d- 的直链, 支链或环状羰基; 含有天然或非天然氨 基酸以及其组成的多肽 C端的羰基。
R5 代表: H; d- 。的直链, 支链或环状羰基; F取代的 d- 直链, 支链或环状羰基; 含有 N原子的 d-C2。的直链, 支链或环状羰基; 含有天然或非天然氨基酸以及其组成的 多肽 C端的羰基。
上述化合物可药用的盐的特征为 (4' -哌啶基哌啶)羰氧基团具有碱性的胺基或天然 或非天然氨基酸的氨基与药用的无机酸或有机酸形成的盐, 这些盐可以使药物成水溶 性。 例如: 盐酸盐、 氢溴酸盐、 磷酸盐、 硫酸盐、 乙酸盐、 三氟乙酸盐、 柠檬酸盐、 马来酸盐、 草酸盐、 琥珀酸盐、 苯甲酸盐、 酒石酸盐、 富马酸盐、 扁桃酸盐、 抗坏血 酸盐、 苹果酸盐、 甲磺酸盐、 对甲苯磺酸盐等。 本发明特别优选的是如下化合物 (CPT1-CPT10):
CPT1: 9-叔丁基氧基乙基肟 -10- [ (4' -哌啶基哌啶)羰氧基] -喜树碱
CPT2: 9-叔丁基氧基乙基肟 -10-羟基-喜树碱
CPT3: 9-叔丁基氧基乙基肟 -10-氟-喜树碱
CPT4: 9-叔丁基氧基乙基肟 -10-苯丙氨酸羰氧基-喜树碱
CPT5: 9-甲基氧基乙基肟 -10-[(4' -哌啶基哌啶)羰氧基] -喜树碱
CPT6: 9-苯基氨基乙基腙 -10- [ (4' -哌啶基哌啶)羰氧基] -喜树碱
CPT7: 9-叔丁基氧基乙基肟-喜树碱
CPT8: 9-叔丁基氧基乙基肟 -10-乙羰氧基] -喜树碱
CPT9: 9-叔丁基氧基乙基肟 -10-[(4' -哌啶基哌啶)羰氧基 ]-20-苯丙氨酸羰氧基-喜 树碱
CPT10: 9-叔丁基氧基乙基肟 -20-苯丙氨酸羰氧基-喜树碱
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000006_0001
2.该类化合物和它们药物组合物
本发明还包括与本发明有效剂量的化合物组成的药物组合物。 所述药物组合物可用于 口服给药和注射给药。
口服给药剂型可以是片剂、 胶囊剂、 口服液、 颗粒剂、 混悬剂等。 口服给药剂型 所用药用敷料为常规敷料, 包括稀释剂、 调味剂、 增溶剂、 润滑剂、 悬浮剂、 粘合剂、 膨胀剂等。
注射剂可是注射液、 粉针剂、 冻干粉、 脂质体等。 注射剂所用药用敷料为常规敷 料, 包括溶剂, 稀释剂、 增溶剂、 PH调节剂等。
有效剂量是指对病人产生有益作用的治疗作用剂量, 其用量依给药途径, 给药方 案而不同。
3. 该类化合物和制备组合在治疗肿瘤中的应用
( 1) .新的喜树碱衍生物在体外的生物活性
用 M T T法检测了 CPT1-CPT10、 伊立替康活性物 (SN-38)、 吉马替康和拓扑替康 在体外对 A549 (非小细胞肺癌), HT-29 (结肠癌), OV-3 (卵巢癌), U87(脑胶质瘤), BX-PC3( 胰腺癌)细胞株的抑制作用。 结果表明, 在 CPT1-10中, CPT1、 CPT4、 CPT5、 CPT6、 CPT9、 CPT10为前体药物,在体外没有明显的活性(未在表中记录)。 CPT2、 CPT3、 CPT7、 CPT8有明显的细胞毒性。
CPT2、 CPT3、 CPT7、 CPT8、 吉马替康、 SN_38、、 拓扑替康对以上对 5种细胞株的 作用从强到弱是 U87、 BX-PC3 HT-29 OV-3、 A549。 以上化合物对 U87 BX-PC3 HT-29 OV-3、 A549抑制 50%细胞生长的平均浓度(nM )分别为: CPT7 (3. 3)、 CPT3 (7. 1)、 吉 马替康(2. 7)、 CPT2 ( 9. 1 )、 SN-38 ( 10. 5)、 CPT8 ( 12. 9)、 拓扑替康 ( 19. 7)。 (见附 表 1)。
(2).新的喜树碱衍生物对人体移植肿瘤的治疗作用:
为了准确评价新的喜树碱衍生物的体内抗肿瘤作用,需要在相同毒性情况下比较抗 肿瘤作用,试验均采用最大耐受剂量 (MTD)进行试验,经试验各药物相同的毒性剂量 (体 重下降均在 15%左右) 是: CPT155mg/kg, q2dx4, 伊立替康 55mg/kg, q2dx4, 吉马替康 lmg/kg, q2dx4, 拓扑替康 12mg/kg, q2dx4。 CP1比 CPT2-10有较好的水溶性和稳定性。 结果表明 CPT1对多种移植肿瘤有好治疗作用。 附图 1: CPT1 对人胰腺癌 BX-PC-3的抗瘤作用
附图 2: CPT1对人结肠癌 HT-29的抗瘤作用
附图 3: CPT1对人非小细胞肺癌 A549的抗瘤作用 具体实施方式
以下通过实施例进一步说明本发明, 但不作为对本发明的限制。 实施例 1: CPT1的具体制备方法:
A. 10-烯丙氧基喜树碱的合成
在装有氩气球的 500 mL两口瓶中加入 10-羟基喜树碱 10.0g (27.5mmol) 和 DMF 200mL,搅拌至固体全溶,再依次加入碳酸钾 5.6g(4. Ommol)和烯丙基溴 2.6mL(3mmol), 氩气保护下, 室温反应 8h。 反应完毕后, 倒入 250ml冰水中, 稀盐酸调节反应 ίΉ=5, 析出黄色固体, 过滤, 100mL*3水洗滤饼, 100mL 乙醚洗, 干燥, 得浅黄色粉末 9.8g (24.2mmol), 收率: 88· 2%。
1誦 R (CDC13) : δ 8.21 (s, 1H) , 8.12 (d, 1H) , 7.62 (s, 1H) , 7.48 (d, 1H) , 7.14(s: 1H), 6. ll(m, 1H), 5.73 (d, 1H) , 5.50 (dd, 1H) , 5.47 (dd, 1H) , 5.30 (m, 1H) , 5.25 (s, 2H), 4.71 (d, 2H), 3.88 (s, 1H) , 1.76 (m, 2H) , 1.03 (t, 3H)。
B. 9-烯丙基 -10-羟基喜树碱的合成
在装有回流冷凝管和氩气球的 1000mL 两口瓶中加入 10-烯丙氧基喜树碱 9.8g (24.2mmol) 和冰醋酸 500mL, 氩气保护下加热回流三天。 减压蒸干, 硅胶柱层析分 离,二氯甲烷: 甲醇 =30: 1 (v/v) 洗脱,得棕黄色粉末 6.4g (15.8mmol), 收率: 65.3% ¾NMR (DMS0-d6) δ 10.19(s, 1H) , 8.61 (s, 1H) , 7.95 (d, 1H), 7.53 (d, 1H), 7.26 (s, 1H), 6.45 (s, 1H) 6.10 (m, 1H) , 5.40 (s, 2H) , 5.23 (s, 2H) , 4.98 (m, 2H) , 3.78 (d, 2H), 1.85 (m, 2H) , 0.88 (t, 3H)
C. 2- (10羟基喜树碱 -9_) 乙醛的合成
500mL 两口瓶中加入 9-烯丙基 -10-羟基喜树碱 6.4g (15.8mmol)、 二氧六环 250mL和水 80mL, 搅拌至固体全溶, 再加入四氧化锇 0.040g (0· 158 ol), 室温搅拌 30分钟后,分批一小时内加入高碘酸钠 16.8g(79. Ommol) 16h后停止反应,力口入 N¾S203 18.0g搅拌半小时,然后将反应倒入 500mL水中,稀盐酸调节 ί¾=5,氯仿萃取(500mL*6 合并氯仿层, 饱和食盐水洗, 无水硫酸钠干燥, 过滤除去N¾S04后, 减压蒸去溶剂, 硅 胶柱层析分离, 洗脱剂为氯仿: 丙酮 =10:1 (v/v), 得淡黄色粉末 3. lg (7.6mmol), 收率: 48.1%
¾ NMR (DMS0-d6) δ 9.79 (s, 1H) , 8.68 (d, 1Η), 7.88 (d, 1H), 7.82 (d, 1H), 7.38 (s, 1H), 6.47 (s, 1H) , 5.41 (s, 2H) , 5.36 (s, 2H) , 5.23 (s, 2H) , 4.32 (s, 2H) , 1.88 (m, 2H), 0.87 (t, 3H)
D. 2- (10羟基喜树碱 -9_) 叔丁醇胺肟的合成
在装有回流冷凝管和氩气球的 250 mL两口瓶中加入 2- (10羟基喜树碱 _9_) 乙 1 3. lg (7.6mmol)、 乙醇 20mL、 叔丁醇胺盐酸盐 1.9g (15.2mmol) 和吡啶 20mL, 氩 气保护下, 90°C搅拌 15h, 反应完毕后, 减压蒸去溶剂, 剩余物硅胶柱层析分离, 洗 脱剂为二氯甲烷: 甲醇 =30: 1 (ν/ν) , 得浅黄色粉末 2. lg (4. lmmol), 收率: 53.9%
1HNMR δ 0.88 (t, H3- + H3- 1· 28 (s, ί-Bu 2) 1.41 (s, ί-Bu β) 1.80-1.90 (m, -E + , 4.32 (s, 2H) , 5.10—5.40 (m, ~E + , 6.53 (s, OH),
7.25-7.50 (m, H— + H— 7.70 (d -E, ) 8.05 (d H— + H— 8.25 (s, ^), 9.0 (s, β) 10.35 (s, 1H)
1. 10- ((4' -哌啶基哌啶) 羰氧基) -9-叔丁醇胺肟乙基喜树碱的合成
哌啶基哌啶氯甲酸酰胺 1.5g (6.5mmol) 溶于 30mL的二氯甲烷中, 将 2- (10羟 基喜树碱 -9-) 叔丁醇胺肟 2. lg (4.4mmol) 溶于 30mL无水吡啶中, 于冰浴中将上述 二氯甲烷溶液加入, 室温搅拌 16h, 反应完后, 减压蒸去溶剂, 剩余物用硅胶柱层析, 得 2. lg黄色固体, 收率: 70. 1%。
¾ NMR (CDC13): δ 8.78 (s, E) , 8.61 (s, Ζ) , 8. 13 (d, 1Η) , 7.66 (d, 1Η), 7.58 (dd, 1H, ), 7.37 (t, E), 6.68 (t, Z) , 5.74 (d, 1H, ) , 5.29 (d, 1H) , 5.26 (s, 2H) , 4.43 (br, 1H), 4.32 (d, 1H, ), 4. 11 (d, Z) , 3.93 (d, E), 3. 1 (t, 1H) , 2.95 (t, 1H) , 2.57 (br, 4H), 1.95 (br, 2H) 1.83(m, 2H) , 1.63 (br, 4H), 1.47 (br, 2H) , 1.27 (s, E), 1.25 (s, Z), 1.03 (t, 3H)。 实施例 2:CPT2-10的制备
制备方法与实施例 1相同, 只是使用的原料是与它们各自取代基相应的化合物。 实施例 3:含有 CPT1的片剂的制备
处方 CPT1 50克
微晶纤维素 100克
乳 糖 100克
淀粉 8克
硬脂酸镁 30克
酸甲基纤维素钠 1克
经制粒压片成 1000片 (50mg/片药)。 实施例 4: 含有 CPT1胶囊的制备
处方 CPT1 50克
微晶纤维素 200克
淀粉 250克
混匀装胶胶囊 1000粒, 含 50mg/粒。 实施例 5:CPT2, CPT3片剂和胶囊的制备
同实施例 3和实施例 4 实施例 6: 在体外对肿瘤细胞的杀伤作用
用 MTT方法测定体外细胞毒性, 取状态良好的细胞, 制成细胞悬液。 取细胞悬液接 种于 96孔板上, 200ul I孔, 置恒温 C 02培养箱中培养 2 4小时。 加入受试药物, 20 ul /孔, 培养 48小时。 将 MT T加入 96孔板中, 20ul /孔, 培养箱中反应 4小时, 吸去上清液, 加入 DMS0, 20 ul /孔, 用酶联免疫检测仪在波长为 570nm处测定每孔 的吸光值, 计算对细胞的杀伤作用。 附表 1 新的喜树碱衍生物在体外对肿瘤细胞的抑制作用
细胞 J 抑制 50%细胞生长浓度 ( ICw nM±SD )
A549 HT-29 0V-3 U87 BX-PC3 平均
CPT2 14.1±1.2 7.1±1.6 16.1±2.5 2.9±1.1 5.1±2.0 9.1
CPT3 11.2±1.0 9.1±3.2 10.1±2.1 2.1± 0 3.1±1.5 7.1
CPT7 5.5±0.8 3.1± 0 4.1±0.4 1.5±0.3 2.1±1.2 3.3
CPT8 19.3±2.2 11.1±1.8 23.1±3.1 4.1±1.7 7.1±2.1 12.9
SN38 16.6±1.9 8.7±1.2 17.1±3.2 3.1±1.1 6.8±2.6 10.5 吉马替康 4.7±0.2 3.6±0.3 3.1±2.2 0.6±0.2 1.5±0.8 2.7 拓扑替康 28.5±3.9 17.3±4.2 21.1±2.6 12.5±3.2 19.1±3.7 19.7
A549:非小细胞肺癌, HT-29:结肠癌, OV-3:卵巢癌, U87:脑胶质瘤, BX-PC3: 胰腺癌 以上化合物对 U87、 BX-PC3、 HT-29、 OV-3、 A549抑制 50%细胞生长的平均浓度( nM ) 分别为: CPT7(3.3)、CPT3(7.1)、吉马替康(2.7)、CPT2(9.1)、SN- 38(10· 5)、CPT8(12.9)、 拓扑替康 (19.7)。 实施例 6 体内抗瘤作用
实验方法: 裸鼠, 雌性。 移植肿瘤:取生长旺盛的肿瘤组织, 用无菌剪刀剪成细 块, 每只接种 50mg的肿瘤组织。 治疗在移植肿瘤后第 6-10天开始, 此时肿瘤重量为 300mg左右。每隔一天称裸鼠体重和测量肿瘤体积。受试移植肿瘤: 人乳腺癌(MX-1), 人非小细胞肺癌 (A549), 人卵巢癌(SK-0V3),人结肠癌 (HT29), 人胰腺癌 (BX_PC_3)。
A:抑瘤率 (%) = (对照组瘤体积一治疗组体积) /对照组体积 X 100%。
B: 肿瘤消失: 肉眼观察不到肿瘤存在, 在实验后 60天。 附表 2 对人乳腺癌 MX-1裸鼠移植瘤的治疗作用
化合物 fi 动物数 T.S(mm3¾ 肿瘤消失 最大体重变化
DO D16# (%) 对照 溶齐 U 6 6 312±34 2100±267 0/6 +6%
CPT1 55 6 6 356±51 0 6/6 -13% 拓扑替康 10 6 6 323±47 124±12 2/6 -14% 伊立替康 60 6 6 361±54 0 6/6 -12% 吉马替康 1 6 6 328±65 0 6/6 -13% 给药方案: 每 2天一次, 共 4次; 给药途径: 尾静脉注射。 #在治疗后的 16天, 肿瘤 消失观察时间为 60天。 用药剂量是经试验后确定的体重下降 12-15%的相同毒性剂量。 T.S:肿瘤体积 附表 3 对人卵巢癌 SK-0V3裸鼠移植瘤的治疗作用
化合物 S 动物数 T.S(mm3) 抑制肿瘤 最大体重变化
mg/kg 始 末 DO D16# ( %) ( % ) 对照 溶剂 6 6 211±24 1823±123 0 +8%
CPT1 55 6 6 236±34 358±34 80.4 -12% 拓扑替康 10 6 6 223±43 1478±226 18.9 -12% 伊立替康 60 6 6 214±26 451±56 75.3 -13% 吉马替康 1 6 6 203±33 578±61 68.4 -12% 给药方案: 每 2天一次, 共 4次; 给药途径: 尾静脉注射。 #在治疗后的 16天。
用药剂量是经试验后确定的体重下降 12-15%的相同毒性剂量。 T.S:肿瘤体积 附表 4 对人脑胶质瘤 U87脑内移植瘤的治疗作用
化合物 週量 动物数 平均活存时间
mg/kg 始 末 (天) 对照 溶剂 10 0 18.6土 1.3
CPT1 55 10 0 26·4±1·2#
伊立替康 60 10 0 22.8+1.4
吉马替康 1 10 0 23.1+1.6 给药方案: 在接种后第 2天给药,每 2天一次, 共 4次; 给药途径: 尾静脉注射。 小鼠 接种 2X105细胞, 小鼠在接种后由于脑内肿瘤而死亡. #:CPT1与伊立替康, 吉马替康 比较,活存时间有明显增加 ,P<0.05.
图 1 : CPT1 , 吉马替康和伊立替康比较抗瘤作用
Figure imgf000012_0001
10 12 14 16 18
Days after implantation
Figure imgf000013_0001
10 12 14 16 18
Days after implantation
Figure imgf000013_0002
人非.小芻嵐歸瘤: ( ίν, inj, ¾2dX4
Figure imgf000013_0003
6 iO 12 14 16 IE 20
S^ys after iimlantatl^i

Claims

权 利 要 求 书
1、 一类具有以下结构式(1)所示结构的抗肿瘤化合物,其异构体,对应体或可药用的盐:
Figure imgf000014_0001
¾ 代表: H; d- 。的直链,支链或环状烷基; F取代的 d- 直链,支链或环状烷基; d- 的直链, 支链或环状酰基; F取代的 d- 直链, 支链或环状酰基; C6-C18的碳芳香环; C6_C18的含有卤原子(F, Cl, Br, I ), 硝基 (N02), 羟基 (OH), 氨基 (NH2), 氰基 (CN) 取代基的碳芳香环; 含有杂原子 (N, 0, S) 的芳香环。
X代表: 0; NH; NR6; R6代表: d- 。的直链, 支链或环状烷基; F取代的 d- 直链, 支 链或环状烷基; d- 。的直链, 支链或环状酰基; F取代的 d-Cw 直链, 支链或环状酰基。 代表: H; d- 。的直链, 支链或环状烷基; F取代的 d- 直链, 支链或环状烷基。 和 '代表:相同或不同的 H; F; d- 。的直链,支链或环状烷基; F取代的 直链, 支链或环状烷基。
R4代表:在 C10位和 C11位相同或不同的 H; 卤素原子 (F, Cl, Br, I ); 硝基 (N02); 羟基 (OH); 氨基 (NH2); d- 。的直链, 支链或环状烷基; F取代的 d- 直链, 支链或 环状烷基; d- 。的直链, 支链或环状酰基; F取代的 d-Cw 直链, 支链或环状酰基; 在 C10位或 C11位的 0R7 ; R7代表: d- 。的直链, 支链或环状羰基; F取代的 d- 直链, 支链 或环状羰基; 含有 N原子的 d- 的直链, 支链或环状羰基; 含有天然或非天然氨基酸以及 其组成的多肽 C端的羰基。
R5 代表: H; d- 。的直链, 支链或环状羰基; F取代的 d- 直链, 支链或环状羰基; 含有 N原子的 d- 的直链, 支链或环状羰基; 含有天然或非天然氨基酸以及其组成的多肽 C端 的羰基。
2、 权利要求 1所述的化合物, 其特征在于,所述化合物选自包括以下化合物的组:
CPT1 : 9- (N-叔丁基氧基) 乙基肟 -10- [ (4' -哌啶基哌啶)羰氧基] -喜树碱
CPT2 : 9- (N-叔丁基氧基) 乙基肟 -10-羟基-喜树碱
CPT3 : 9- (N-叔丁基氧基) 乙基肟 -10-氟-喜树碱 CPT4: 9- (N-叔丁基氧基) 乙基肟 -10-苯丙氨酸羰氧基-喜树碱
CPT5: 9- (N-甲基氧基) 乙基肟 -10- [(4' -哌啶基哌啶)羰氧基] -喜树碱
CPT6: 9- (N-苯基氨基) 乙基腙 -10- [ (4' -哌啶基哌啶)羰氧基] -喜树碱
CPT7: 9- (N-叔丁基氧基) 乙基肟-喜树碱
CPT8: 9- (N-叔丁基氧基) 乙基肟 -10-乙羰氧基] -喜树碱
CPT9: 9- (N-叔丁基氧基) 乙基肟 -10-[(4' -哌啶基哌啶)羰氧基 ]-20-苯丙氨酸羰氧基- 喜树碱
CPT10: 9- (N-叔丁基氧基) 乙基肟 -20-苯丙氨酸羰氧基-喜树碱
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000016_0001
3、 权利要求 1所述的化合物的制备方法由如下步骤组成:
Figure imgf000016_0002
a. 10-羟基喜树碱和相应取代反应得到醚类化合物 A;
b. Claisen重排反应得到化合物 B;
c 氧化反应得到化合物 C;
d. 缩合反应得到化合物 D;
e. 酯化反应得到化合物 1。
4、权利要求 1的化合物的药学上可接受的盐, 可以是该化合物与无机酸或有机酸所形成 的盐, 所述盐选自盐酸盐、 氢溴酸盐、 磷酸盐、 硫酸盐、 乙酸盐、 三氟乙酸盐、 柠檬酸 盐、 马来酸盐、 草酸盐、、 苯甲酸盐、 酒石酸盐、 富马酸盐、 甲磺酸盐等。
5、一种药物组合物, 其特征在于包括治疗有效剂量的权利要求 1所述的化合物和常规的 药用辅料。
6、权利要求 4所述的药物组合物, 其特征在于所述药物组合物被制备为口服或注射剂型。
7、 权利要求 1所述的喜树碱类衍生物的制备和在治疗肿瘤疾病的药物中的应用。 International application No.
INTERNATIONAL SEARCH REPORT
PCT/CN2012/073578
A. CLASSIFICATION OF SUBJECT MATTER
See the extra sheet
According to International Patent Classification (PC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
IPC: C07D, A61K, A61P
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
WPI, EPODOC, CPRS, CNKI, CSPD, REGISTRY, CAPLUS, MARPAT: LEI, Xiaoguang; ZHANG, Xiuguo; CPT, camptothecin. ethyl oxime, ethyl hydrazone, structure searching
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
A CN 101407516 A (LEI, Xiaoguang), 1 April 2009 (15.04.2009), the whole document 1-7 A CN 1616460 A (SHANGHAI INSTITUTE OF MATERIA MEDIC A, CHINESE 1-7
ACADEMY OF SCIENCES), 18 May 2005 (18.05.2005), the whole document
□ Further documents are listed in the continuation of Box C. 13 See patent family annex.
* Special categories of cited documents: T" later document published after the international filing date or priority date and not in conflict with the application but
"A" document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention
"E" earlier application or patent but published on or after the "X" document of particular relevance; the claimed invention international filing date cannot be considered novel or cannot be considered to involve an inventive step when the document is taken alone
;iL" document which may throw doubts on priority claim(s) or
"Y" document of particular relevance; the claimed invention which is cited to establish the publication date of another
cannot be considered to involve an inventive step when the citation or other special reason (as specified) document is combined with one or more other such
Ό" document referring to an oral disclosure, use, exhibition or documents, such combination being obvious to a person other means skilled in the art
"&,, document member of the same patent family
"P,, document published prior to the international filing date
but later than the priority date claimed
Figure imgf000017_0001
Form PCT ISA/210 (second sheet) (July 2009) INTERNATIONAL SEARCH REPORT International application No.
Information on patent family members
PCT/CN2012/073578
Patent Documents referred
Publication Date Patent Family Publication Date in the Report
CN 101407516 A 15.04.2009 None
CN 1616460 A 18.05.2005 WO 2005044821 Al 19.05.2005
CN 100406460 C 30.07.2008
Form PCT ISA/210 (patent family annex) (July 2009)
PCT/CN2012/073578 2011-04-07 2012-04-06 一类具有抗肿瘤活性的喜树碱衍生物 WO2012136144A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2014502977A JP5755796B2 (ja) 2011-04-07 2012-04-06 抗腫瘍活性を有するカンプトテシン誘導体
RU2013149416/04A RU2561118C2 (ru) 2011-04-07 2012-04-06 Производные камптотецина, обладающие противоопухолевой активностью
US14/006,102 US9006439B2 (en) 2011-04-07 2012-04-06 Camptothecin derivatives having anti-tumor activity
KR1020137020846A KR101575079B1 (ko) 2011-04-07 2012-04-06 일종의 항종양 활성을 갖는 캄프토테신 유도체
EP12768102.1A EP2695884B1 (en) 2011-04-07 2012-04-06 Camptothecin derivatives having anti-tumor activity

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CN201110086102.6A CN102731516B (zh) 2011-04-07 2011-04-07 一类具有抗肿瘤活性的喜树碱衍生物
CN201110086102.6 2011-04-07

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CN102731516B (zh) 2011-04-07 2014-07-02 宁波天衡药业股份有限公司 一类具有抗肿瘤活性的喜树碱衍生物
CN109400619A (zh) * 2018-12-25 2019-03-01 东北林业大学 10-甲氧基喜树碱水溶性衍生物、制备方法和用途
CN112773812A (zh) * 2020-12-30 2021-05-11 烟台大学 新型喜树碱衍生物制备抗肿瘤药物的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1616460A (zh) * 2003-11-10 2005-05-18 中国科学院上海药物研究所 喜树碱的新衍生物、制备方法和用途
CN101407516A (zh) * 2008-10-06 2009-04-15 雷晓光 具有抗癌活性的喜树碱衍生物

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9316352D0 (en) * 1993-08-06 1993-09-22 Erba Carlo Spa Process for the preparation of 9-amino camptothecin
JPH08333370A (ja) * 1995-06-08 1996-12-17 Kyorin Pharmaceut Co Ltd 水に可溶な新規フルオロエチルカンプトテシン誘導体、及びその製造方法
IT1282673B1 (it) * 1996-02-23 1998-03-31 Ist Naz Stud Cura Dei Tumori Derivati della camptotecina e loro uso come agenti antitumorali
US7105492B2 (en) * 1999-03-09 2006-09-12 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Camptothecin derivatives having antitumor activity
KR101367516B1 (ko) * 2004-12-15 2014-02-27 씨그마-토 인더스트리에 파마슈티체 리유니테 에스. 피. 에이. 암치료용 치료제의 조합물
CN101033230B (zh) * 2006-03-10 2010-12-08 中国科学院上海药物研究所 一类喜树碱衍生物及其应用
EP2096113A1 (en) * 2008-02-05 2009-09-02 SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A. 9-substituted camptothecin derivatives as antitumor compounds
CN101407515A (zh) * 2008-11-24 2009-04-15 深圳市盛捷生物技术有限公司 用作cdk抑制剂的喹啉类多环化合物
CN102731516B (zh) 2011-04-07 2014-07-02 宁波天衡药业股份有限公司 一类具有抗肿瘤活性的喜树碱衍生物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1616460A (zh) * 2003-11-10 2005-05-18 中国科学院上海药物研究所 喜树碱的新衍生物、制备方法和用途
CN101407516A (zh) * 2008-10-06 2009-04-15 雷晓光 具有抗癌活性的喜树碱衍生物

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RU2561118C2 (ru) 2015-08-20
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