WO2013170719A1 - 长春瑞滨衍生物、其药物组合物及其制备方法和用途 - Google Patents
长春瑞滨衍生物、其药物组合物及其制备方法和用途 Download PDFInfo
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- WO2013170719A1 WO2013170719A1 PCT/CN2013/075350 CN2013075350W WO2013170719A1 WO 2013170719 A1 WO2013170719 A1 WO 2013170719A1 CN 2013075350 W CN2013075350 W CN 2013075350W WO 2013170719 A1 WO2013170719 A1 WO 2013170719A1
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- acid
- preparation
- vinorelbine
- cancer
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
-
- 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
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- Vinorelbine derivative pharmaceutical composition thereof, preparation method and use thereof
- the present invention relates to a vinorelbine derivative which can treat a tumor, a pharmaceutical composition thereof, a preparation method thereof and use thereof.
- Malignant tumors are the most important diseases that threaten human health after cardiovascular disease. Worldwide, the number of deaths caused by disease is 15% of the total deaths, and this ratio is 25% in developing countries. Currently, an average of nearly 80,000 people die each year from malignant tumors. Therefore, in the face of the increasingly serious malignant tumor crisis, countries around the world are working hard to improve the status of cancer treatment in the world, especially in developing countries.
- the vinblastine compound is a dimeric steroidal alkaloid and is an important cell cycle-specific antitumor drug mainly used for the treatment of Hodgkin's disease, breast cancer, non-small cell lung cancer and the like.
- Changchun's mechanical drugs can interfere with the mitotic phase (M phase) of the cell cycle, thereby inhibiting cell division and proliferation. Its cytotoxicity is achieved by binding to tubulin, which has a common binding site on the tubulin dimer, which inhibits microtubule polymerization and prevents the formation of spindle microtubules, thereby allowing cell division in the medium term. Stop, prevent cancer cells from dividing and proliferating.
- Vinblastine (vinblastine, VLB) and vincristine (vincristine, VCR) was first isolated from the oleander plant flowers Chief (Catharanth roseus LG Don) bis antineoplastic indole alkaloids in clinical ⁇ It has been widely used for more than 40 years. Due to the small changes in their structure leading to great differences in their toxicity and therapeutic tumor spectrum, efforts have been made to discover broad-spectrum, high-efficiency, low-toxic neo-vinblastine antitumor drugs through structural modification. Up to the end of II, three semi-synthetic vinblastine drugs have been developed and marketed: vindesine, vinorelbine and vinflunine.
- vinblastine vinorelbine The third-generation vinblastine vinorelbine (Vinorelbine;), developed by the French Pierre Fabre laboratory, has become the first line of clinical treatment for non-small cell lung cancer (S. Cros, el al, Seminars in Oncology, 1989, 16). : 15-20.), compared with vinblastine, vincristine, and vindesine, it has the advantages of anti-tumor, small toxic side effects and high chemical stability. In addition to its use in non-small cell lung cancer, vinorelbine has also shown therapeutic potential for metastatic breast cancer and refractory lymphoma, ovarian cancer, head and neck cancer and other tumors.
- CN200710036923.2 discloses a novel derivative of vinorelbine having a structural formula of a 9-membered ring and having an anticancer effect, but the structure of the 9-membered ring is not stable enough.
- the application also discloses the use of Wendolin as a starting material, synthetic formula (II)
- a novel vinorelbine derivative or a pharmaceutically acceptable salt thereof is provided.
- the vinorelbine derivative not only has similar or better medicinal properties than vinorelbine, but also has better stability, and is important in improving anti-tumor selectivity, optimizing drug characteristics, expanding anti-tumor spectrum, and the like.
- Development prospects, a second object of the present invention is to provide a pharmaceutical composition comprising the above vinorelbine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- a third object of the present invention is to provide a process for the preparation of the above-mentioned vinorelbine derivative, which is based on Wendolin as a starting material, and finally a compound having an 8-membered ring more stable structure is obtained by enthalpy.
- a fourth object of the present invention is to provide a use of the above vinorelbine derivative or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a tumor.
- a fifth object of the present invention is to provide the above vinorelbine derivative or a pharmaceutically acceptable salt thereof for use in the treatment of a tumor.
- a sixth object of the present invention is to provide a method of treating a tumor by administering to the patient a therapeutically effective amount of the above vinorelbine derivative or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.
- c r c 6 is an alkoxy group
- R 2 is OR 3 or NR 4 R 5 ; wherein is 11, C r C 6 alkanoyl or aromatic acyl group, and R 5 are each independently 11, - alkanoyl, C 3 - C 6 cycloalkanoyl, aromatic acyl or C a 3- C 6 heteroaromatic fluorenyl group; the aryl group in the aromatic fluorenyl group in R 3 , R 4 R 5 is a phenyl group or 1-4 selected from the group consisting of halogen, methyl, trifluoromethyl and methoxy The group in the group is substituted with a phenyl group, and the hetero atom in the C 3 -C 6 heteroaroyl group is 1-3 atoms selected from the group consisting of 0, S and N.
- the vinorelbine derivative is preferably: acetyl, R 2 is acetate, p-fluorobenzoate, o-fluorobenzoate, p-methoxybenzoate, acetamide , propionamide, butyramide, isobutyramide, pentanoamide, cyclopropionamide, benzamide, p-fluorobenzamide, o-fluorobenzamide, 2,6-difluorobenzene Amide amide, p-benzoic acid amide, o-methoxy benzamide, p-methoxyphenyl amide, m. Benzobenzamide, 3,4-dimethoxybenzamide, p-methylbenzoinamide, p-trifluoromethylphenyl amide or oxime amide.
- the vinorelbine derivative is also preferably: a propionyl group and R 2 is a propionamide group.
- the present invention also provides a pharmaceutically acceptable salt of the above vinorelbine derivative.
- the pharmaceutically acceptable salt of the vinorelbine derivative may be a salt obtained by addition of an acid or a salt obtained by addition with a base.
- the present invention is not particularly limited to an acid or a base which can be used to form a pharmaceutically acceptable salt.
- the acid may be hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, tartaric acid, sulphuric acid Acid or isethionic acid;
- the base may be sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, ammonia, triethylamine or triethanolamine.
- a pharmaceutical composition for treating a tumor comprising a therapeutically effective amount of at least one compound selected from the above-described vinorelbine derivatives and a pharmaceutically acceptable salt thereof as an active ingredient is provided.
- the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, adjuvant and/or adjuvant.
- a pharmaceutically acceptable carrier excipient, adjuvant and/or adjuvant.
- the carrier, excipient, adjuvant and/or adjuvant may be those conventionally used in the art, and thus will not be described herein.
- the pharmaceutical composition of the present invention may further comprise a therapeutically effective amount of another pharmaceutically acceptable therapeutic agent as an active ingredient to constitute a combination preparation.
- a process for the preparation of the above vinorelbine derivative or a pharmaceutically acceptable salt thereof comprising the steps of:
- a compound of formula II is acylated and/or amidated to give an intermediate compound of formula HI;
- the intermediate compound shown by ⁇ is coupled with vinblastine in a buffer solution to obtain an intermediate product VI;
- the intermediate product VI is further condensed to obtain a vinorelbine derivative;
- R 2 is the same as defined above.
- the solvent used in the acylation in step a may be dichloromethane, chloroform or tetrahydrofuran, and the temperature of the acylation reaction may be 0 room temperature depending on the reaction of the specific compound.
- the alkali-based reagent used in the acylation reaction may be sodium hydride (NaH), pyridine or a 33% aqueous solution of sodium acetate, and the acylating agent may be an acid anhydride, an acid chloride or an acid chloride.
- a ligand formed by benzotriazole may be sodium hydride (NaH), pyridine or a 33% aqueous solution of sodium acetate, and the acylating agent may be an acid anhydride, an acid chloride or an acid chloride.
- a ligand formed by benzotriazole may benzotriazole.
- the buffer solution used for coupling is an aqueous solution of sodium sulphate having a pH of about 1.3.
- the key intermediate II or III is obtained by the reaction route disclosed in Chinese Patent Application No. CN200710036923.2.
- the method includes the following steps:
- reaction synthesis route of the above-mentioned intermediate compounds ruthenium and osmium is as follows:
- the intermediate compound H or IH is subjected to a series of reactions such as acylation to give intermediate compounds a-01 a- 04 and b- 01 - b-19 which are described in detail below.
- the intermediate compounds a-01 ⁇ a-04 and b-01 - b-19 are then coupled with vinblastine.
- brominated in the bromination reaction solution and then condensed in a tetrahydrofuran aqueous solution by a cyclization reagent tetrafluoroboric acid to obtain a vinorelbine derivative of the ruthenium and osmium series according to the present invention, and the yield is 50-80. %.
- the degree of completion of the reaction is usually detected by TLC and LC-MS. After completion of the reaction, it is usually extracted with a solvent such as ethyl acetate or dichloromethane, and washed successively with sodium hydrogencarbonate, water and brine, and dried over anhydrous sodium sulfate. The intermediate product and the final product were detected by nuclear magnetic resonance and mass spectrometry.
- a solvent such as ethyl acetate or dichloromethane
- a fourth aspect of the present invention there is further provided the use of the above vinorelbine derivative or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a malignant tumor.
- a vinorelbine represented by the above formula I for use in the treatment of a malignant tumor ⁇ Biological or a pharmaceutically acceptable salt thereof.
- a method for treating a malignant tumor comprising administering to a patient a therapeutically effective amount of the above-described vinorelbine derivative or a pharmaceutically acceptable salt thereof; or administering the above pharmaceutical composition, wherein the therapeutically effective
- the at least one compound selected from the above-described vinorelbine derivatives and pharmaceutically acceptable salts thereof is used as an active ingredient.
- the vinorelbine derivative of the present invention or a pharmaceutically acceptable salt thereof may be in an amorphous form or in any form of crystal or mixed crystal unless otherwise specified; it may be a compound or a salt itself, or may be It is in the form of a hydrate or a solvate; or it may be a suitable prodrug.
- the (malignant) tumors treated with the vinorelbine derivative of the present invention or a pharmaceutically acceptable salt thereof may be lung cancer, breast cancer, liver cancer, gastric cancer, esophageal cancer, colon cancer, leukemia. , lymphoma, prostate cancer, kidney cancer, skin cancer, pancreatic cancer, ovarian cancer, brain cancer, bone marrow cancer or fibrosarcoma; especially lung cancer or cervical cancer.
- the invention designs and synthesizes a novel class of vinorelbine derivatives, which have good inhibitory activity on cell proliferation of human A-549 lung cancer, human HeLa cervical cancer and other tumor cell lines, and has good stability and can be used for preparation.
- the compound of the invention is simple in synthesis, easy to prepare, and rich in synthetic raw materials. detailed description
- the preparation method was the same as that described in Preparation Example 8, except that the acid chloride used was n-pentanoyl chloride instead of propionyl chloride, and the yield was 71%.
- the preparation method was the same as that described in Preparation Example 8, except that the acid chloride used was cyclopropyl decanoyl chloride in place of propionyl chloride, and the yield was 74%.
- the preparation method was the same as that described in Preparation Example 8, except that the acid chloride used was benzoyl chloride in place of propionyl chloride, and the yield was 76%.
- the preparation method was the same as that described in Preparation Example 8, except that the acid chloride used was p-fluorobenzoyl chloride instead of propionyl chloride, and the yield was 77 ° / 0 .
- the preparation method was the same as that described in Preparation Example 8, except that the acid chloride used was o-fluorobenzoyl chloride in place of propionyl chloride, and the yield was 73%.
- the preparation method was the same as that described in Preparation Example 8, except that the acid chloride used was 2,6-difluorobenzoyl chloride in place of propionyl chloride in a yield of 70%.
- the preparation method was the same as that described in Preparation Example 8, except that the acid chloride used was p-methoxybenzoyl chloride in place of propionyl chloride, and the yield was 76%.
- the preparation method was the same as that described in Preparation Example 8, except that the acid chloride used was m-methoxybenzoyl chloride in place of propionyl chloride, and the yield was 73%.
- the concentrate was recrystallized from methanol or purified by silica gel column chromatography (50: 1-100:1, CHCl 3 /MeOH) to yield 2.29 g of Compound A-01 (white solid); The purity was greater than 98% by HPLC.
- Test Example 1 In vitro antitumor activity test of the compound of the present invention
- Cell line A549 human non-small cell lung cancer cell line (purchased from ATCC)
- Positive control drug vinorelbine tartrate (prepared according to conventional methods); purity was more than 98% by HPLC-UV, and the structure was confirmed by NMR. And the positive control test compound was diluted with physiological saline, a concentration gradient 1CT 4 M, IO- 5 M, 10- 6 ⁇ , 1 ( ⁇ 7 ⁇ , 10 "8 ⁇ " experimental method:
- the cell viability is detected by the MTS method.
- the principle is consistent with the principle of the MTT method. The difference is that the components in the MTS assay kit (Promega, cat#G5421) react with the cells to form a soluble konjac with maximum absorption at 490 nm.
- the advantage of this method is that it does not kill the cells and can be tested from time to time without removing the medium. Cell viability was calculated by measuring the absorbance at 490 nm.
- A549 cells were cultured in vitro with RPMI-1640 medium containing 10% FBS, 2 mM glutamine, 10 mM HEPES, 0.11 g/L sodium pyruvate, lx l0 5 U/L penicillin, 1 ⁇ 10 g/L chain Mycin.
- the cells in the logarithmic growth phase were collected, and the cell viability was measured by trypan blue, and then seeded in a 96-well microplate.
- 37. C 5% C0 2 conditions for 48-72 hours, add MTs solution 30 ⁇ / well, continue to culture for 1-4 hours.
- the OD490 was detected by a multi-function microplate reader (Molecular device SpectraMax M5).
- the inhibition rate of tumor cells on tumor cell growth was calculated according to the following formula.
- Cell line A549 human non-small cell lung cancer cell line (purchased from ATCC) renew
- Test animals Balb/C rats, male, 6 weeks old, purchased from Beijing Huakangkang Biotechnology Co., Ltd.
- the bait is raised in the SPF environment, the temperature is 20 ⁇ 25 'C, the relative humidity is 40 ⁇ 70%, and the 12:12h light and dark lighting; free drinking water and feeding.
- Vinorelbine and the test drugs (B-08, B-19) were prepared by synthetic methods with a purity of >98%.
- A549 cells were cultured and expanded in vitro, and the cells in logarithmic growth phase were collected, resuspended in serum-free F-12K medium and inoculated into the right forelimb of the right forelimb of nude mice. After 22 days, the tumor grew to about 260 mm 3 before the tumor was tumor.
- Tumor-bearing mice were grouped into groups (6/group) by random block method, including solvent control group, positive control vinorelbine (NVB) group, and test sample group. The drug was administered intravenously (iv) once, and tumor growth was observed.
- B-08 and B-19 showed some inhibition on A549 transplanted tumors. At the same dose, B-19 had higher antitumor activity than NVB.
- Cell line Human breast cancer MDA-MB-231, from the Chinese Academy of Sciences cell bank.
- Test animals Balb/C rats, female, 6 weeks old, purchased from Beijing Huakangkang Biotechnology Co., Ltd. The word is raised in SPF environment, temperature 20 ⁇ 25 °C, relative humidity 40 ⁇ 70%, 12: 12h light and dark lighting; free drinking water and feeding. Both vinorelbine and the test drug (B-14) were prepared by a synthetic method with a purity of >98%.
- MDA-MB-231 cells were cultured and expanded in vitro, and the cells in logarithmic growth phase were collected, resuspended in DMEM serum-free medium and inoculated subcutaneously into the right forelimb of the mouse. After 14 days, the tumor grew to about 250 mm 3 ; The tumor-bearing mice were divided into groups by random block method, and the saline control group was injected with saline injection once a week. The positive control NVB and the test drug B-14 were administered intravenously (iv). The tumor growth was observed once a week for 21 consecutive days.
- Each of the above prepared solutions was accurately aspirated for 10 ⁇ , and the change in peak area of the samples was examined for 0 and 6 hours to examine the stability of the sample.
- the purity of the sample at 100 hours was set to 100%, and the peak area of the sample at 6 hours divided by the peak area of the sample at 0 hours was the purity of the sample at 6 hours.
- the octadecyl silane-bonded silica gel was used as a filler; the mobile phase was acetonitrile-water (50 mM KH 2 P0 4 + 5 mM sodium dodecyl sulfate) (50:50); the flow rate was 1 ml/min; The detection wavelength is 266 nm; the column temperature is 40. C. Table 2. Compounds disclosed in CN200710036923.2
Abstract
本发明公开了具有下式（I）所示结构的长春瑞滨衍生物或其可药用的盐，以及含治疗有效量的所述长春瑞滨衍生物或其可药用的盐的药物组合物；还公开了所述长春瑞滨衍生物或其可药用的盐的制备方法及其在制备治疗肿瘤的药物中的应用。所述长春瑞滨衍生物对多种人源肿瘤细胞株具有抑制活性，可作为治疗恶性肿瘤的药物。
Description
长春瑞滨衍生物、 其药物组合物及其制备方法和用途
本发明涉及一种可治疗肿瘤的长春瑞滨衍生物、 其药物组合物及其制备方法和用 途。 背景技术
恶性肿瘤是继心血管病之后成为威胁人类健康的最主要疾病。 在世界范围内， 由 读疾病导致的死亡人数占总死亡人数的 15%, 而这一比率在发展中国家达到了 25%, 目前平均每年近 80Q 万人死于恶性肿瘤。 因此， 面对日益严峻的恶性肿瘤危机， 世界 各国都在努力改善全球尤其是发展中国家肿瘤治疗现状。
长春碱类化合物是二聚吲哚类生物碱， 是一类重要的细胞周期特异性抗肿瘤药物， 主要用于治疗何杰金氏病、 乳腺癌、 非小细胞性肺癌等。 长春械类药物可干扰细胞周 期的有丝分裂阶段 (M期)， 从而抑制细胞的分裂和增殖。其细胞毒性是通过与微管蛋白 的结合实现的， 它们在微管蛋白二聚体上有共同的结合位点， 可抑制微管聚合， 妨碍 纺锤体微管的形成， 从而使细胞分裂于中期停止， 阻止癌细胞分裂增殖。
长春碱 (vinblastine, VLB) 和长春新碱 (vincristine, VCR) 最早是从夹竹桃科长春 花（ Catharanth roseus L G Don )植物中分离得到的双吲哚生物碱类的抗肿瘤药物 } 在临床上已经被广泛使用了 40多年。 由于它们结构的微小变化导致其毒性以及治疗瘤 谱的极大不同， 因此， 人们致力于通过结构修饰以期发现广谱、 高效、 低毒的新长春 碱类抗肿瘤药物。 到 II前为止， 相继已有 3种半合成的长春碱类药物被开发上市： 长 春地辛、 长春瑞滨和长春氟宁。
由法国 Pierre Fabre实验室开发的第三代长春碱类药物长春瑞滨 （ vinorelbine；)， 已 成为临床上治疗非小细胞肺癌的一线药物（S. Cros, el al, Seminars in Oncology, 1989, 16: 15-20。）， 其与长春碱、 长春新碱、 长春地辛相比， 具有抗瘤谙广、 毒副作用小和 化学稳定性高等优点。 除了用于非小细胞肺癌， 长春瑞滨对转移性乳腺癌及难治性淋 巴瘤、 卵巢癌、 头颈部肿瘤等肿瘤也显示出治疗前景。
CN200710036923.2公开了一种长春瑞滨新衍生物，该衍生物具有 9元环的结构式， 具有抗癌的作用， 但 9元环的结构不够稳定。 该申请中还公开了以文朵灵为起始原料， 合成式 （II)
因此， 本发明的目的之一是提供一种新的长春瑞滨衍生物或其可药用的盐。 所述 长春瑞滨衍生物不但具有类似或更优于长春瑞滨的药物特性， 而且具有更好的稳定性 , 在提高抗肿瘤选择性、 优化药物特性、 扩展抗肿瘤谱等方面具有重要意义和开发前景， 本发明的第二个目的是提供一种以上述长春瑞宾衍生物或其可药用的盐为活性成 分的药物組合物。
本发明的第三个目的是提供上述长春瑞宾衍生物的制备方法， 该方法以文朵灵为 起始原料， 最后通过缩钚获得具有 8元环更稳定结构的化合物。
本发明的第四个目的是提供上迷长春瑞宾衍生物或其可药用的盐在制备治疗肿瘤 的药物中的应用。
本发明的第五个目的是提供用于治疗肿瘤用途的上述长春瑞宾衍生物或其可药用 的盐。
本发明的第六个目的是提供一种通过对患者施用治疗有效量的上述长春瑞滨衍生 物或其可药用的盐、 或者上述药物组合物来治疗肿瘤的方法。
根据本发明第一 I) 的长春瑞宾衍生物：
1
其中 为 crc6烷酰基；
R2为 OR3或 NR4R5; 其中 为 11、 CrC6烷酰基或芳香酰基， 、 R5各自独立地 为11、 -^烷酰基、 C3-C6环烷酰基、 芳香酰基或 C3-C6杂芳香跣基； R3、 R4 R5中所 述芳香跣基中的芳香基为苯基或者被 1-4个选自由卤素、 甲基、三氟曱基和甲氧基所组 成组中的基团取代的苯基， 且所述 C3-C6杂芳香酰基中的杂原子是 1-3个选自由 0、 S 和 N所组成组中的原子。
该长春瑞滨衍生物优选为： 为乙酰基， R2为乙酸酯基、 对氟苯甲酸酯基、 邻氟 苯曱酸酯基、 对甲氧基苯甲酸酯基、 乙酰胺基、 丙酰胺基、 丁酰胺基、 异丁酰胺基、 戊酰胺基、 环丙甲酰胺基、 苯甲酰胺基、 对氟苯甲酰胺基、 邻氟笨甲酰胺基、 2，6-二氟 苯曱酰胺基、 对氣苯甲酰胺基、 邻甲氧基苯甲酰胺基、 对甲氧基苯曱酰胺基、 间曱氧
基苯甲酰胺基、 3,4-二甲氧基苯曱酰胺基、 对甲基苯曱酰胺基、 对三氟曱基苯曱酰胺基 或者糠酰胺基。
该长春瑞滨衍生物还优选为： 为丙酰基， R2为丙酰胺基。
B-01 B-02
B-19
本发明还提供上述长春瑞滨衍生物可药用的盐。 该长春瑞宾衍生物可药用的盐可 为与酸加成得到的盐或与碱加成得到的盐。 本发明对可用于形成可药用盐的酸或碱没 有特别的限制。 举例来说， 所述酸可为盐酸、 硫酸、 磷酸、 乙酸、 柠檬酸、 草酸、 丙 二酸、 水杨酸、 苹果酸、 富马酸、 琥珀酸、 抗坏血酸、 马来酸、 酒石酸、 曱磺酸或羟 乙磺酸； 所述碱可为碳酸钠、 碳酸钾、 氢氧化钠、 氢氧化钾、 氨、 三乙胺或三乙醇胺。
根据本发明的第二方面， 提供一种用于治疗肿瘤的药物组合物， 其中含有治疗有 效量的至少一种选自上述长春瑞宾衍生物和其可药用的盐的化合物作为活性成分。
所述药物组合物可进一步包括可药用的载体、 赋形剂、 佐剂和 /或辅料。 所述载体、 赋形剂、 佐剂和 /或辅料可为本领域常规使用的那些， 因而在此不再赘述。
冲艮据本发明的一种实施方式， 本发明的药物组合物， 可进一步包括治疗有效量的 其它可药用的治疗剂作为活性成分， 组成复方制剂。
根据本发明的第三方面， 提供上述长春瑞滨衍生物或其可药用的盐的制备方法， 该方法包括如下步骤：
a.
Ill
a、 式 II所示化合物经酰化和 /或酰胺化得到式 HI所示中间化合物；
b、 式 ΠΙ所示中间化合物与长春 碱在緩冲溶液中偶合得到中间产物 VI； c、 中间产物 VI进一步经缩环得到长春瑞滨衍生物；
其中 和 R2与以上定义相同。
优选地， 在根据本发明的方法中， 步骤 a中， 酰化所采用的溶剂可为二氯甲烷、 氯 仿或四氢呋喃， 并且根据具体化合物的反应情况， 酰化反应的温度可为 0 室温。
优选地， 在根据本发明的方法中， 酰化反应所采用的碱类反应试剂可为氢化钠 ( NaH )、 吡啶或 33%的乙酸钠水溶液， 并且酰化剂可为酸酐、 酰氯或酰氯与苯并三氮 唑生成的配体。
优选地， 在根据本发明的方法中， 步骤 b中， 偶合所用的緩冲溶液为 pH约为 1.3 的硫酸 钠水溶液。
具体地， 根据本发明的方法， 以文朵灵为原料， 经由中国专利申请 CN200710036923.2中公开的反应路线得到关键中间体 II或 III。
具体地， 所述方法包括以下步骤：
1 ) 以下式所示的文朵灵为原料， 经还原得到中间体化合物 II；
2 ) 中间体化合物 II经过环氧化、 叠氮取代和还原后得到化合物 II，；
3 )化合物 II经烷基化得到 R2为 OR3的中间体化合物 III； 化合物 II，经酰化得到 为 NR4R5的中间体化合物 III。
根据一种具体实施方式， 上述制备中间体化合物 Π和 ΠΙ的反应合成路线如下：
Hi
fl' HI 根据本发明的实例，中间体化合物 H或 IH经过酰基化等一系列反应，得到下文中详 述的中间体化合物 a-01 a- 04和 b- 01 - b-19。 中间体化合物 a-01 ~ a-04和 b-01 - b-19 再与长春质碱偶合。 最后在溴代反应液中溴代， 然后在四氢呋喃水溶液中， 通过缩环 试剂四氟硼酸 而缩环， 得到本发明所述的 Α和 Β 系列的长春瑞滨衍生物， 得率在 50-80%。 通常用 TLC以及 LC-MS来检测反应完成程度。 反应完毕后一般用乙酸乙酯 或二氯甲烷等溶剂萃取， 依次用 和碳酸氢钠、 水、 饱和食盐水洗， 经无水硫酸钠千 燥后， 低温减压下除去溶剂。 中间产物及最终产物用核磁共振以及质谱检测。
根据本发明的第四方面，还提供上述长春瑞滨衍生物或其可药用的盐在制备治疗恶 性肿瘤的药物中的应用。
根据本发明的第五方面,同时提供用于治疗恶性肿瘤用途的上述式 I 所示长春瑞滨
^^生物或其可药用的盐。
根据本发明的第六方面， 提供一种治疗恶性肿瘤的方法， 包括对患者施用治疗有效 量的上述长春瑞滨衍生物或其可药用的盐； 或者施用上述药物组合物， 其中含有治疗 有效量的至少一种选自上述长春瑞宾衍生物和其可药用的盐的化合物作为活性成分。
本文中，如无特别说明，本发明的长春瑞滨衍生物或其可药用的盐可以是非晶形式， 也可以是任何结晶或混晶的形式； 可以是化合物或其盐本身， 也可以是以水合物或溶 剂化物形式存在； 或者可以是适宜的前药。
如无特别说明 ,本文提及的采用本发明的长春瑞滨衍生物或其可药用的盐所治疗的 (恶性）肿瘤可为肺癌、 乳腺癌、 肝癌、 胃癌、 食道癌、 结肠癌、 白血病、 淋巴癌、 前列腺癌、 肾癌、 皮陝癌、 胰腺癌、 卵巢癌、 脑癌、 骨髓癌或纤维肉瘤； 特別是肺癌 或宫颈癌。
本发明设计并合成了一类新型的长春瑞滨衍生物，其对人源 A-549肺癌、人源 HeLa 宫颈癌等肿瘤细胞株细胞增殖具有良好的抑制活性， 而且稳定性好， 可用于制备治疗 恶性肿瘤的药物。 本发明化合物合成简单， 易于制备， 且合成原料丰富。 具体实施方式
下面结合具体实施例对本发明作进一步阐述， 但不限制本发明。 本发明的实验操作 具有通用性， 不限于以下实施例中提到的具体化合物。
下述制备例中 , 1H-NMR用 Varian Mercury AMX300型仪测定。 MS用 VG ZAB-HS 或 VG- 7070型以及 Esquire 3000 plus- 01005测定。 所有溶剂在使用前均经过重新蒸馏， 所使用的无水溶剂均是按标准方法干燥处理获得。 除特别说明外， 所有反应均是在氩 气保护下进行并用 TLC跟踪， 后处理时均经饱和食盐水洗和无水硫酸钠干燥过程。 产 品的纯化除说明外均使用硅胶 ( 200-300 目）柱色谱法， 所使用的硅胶为 200-300目，
GF2S4 (青岛海洋化工厂或烟台缘博硅胶公司生产）。 制备实施实例
制备实施实例 1
中间 II的制备：
在氢气保护下， 取 456 mg (l mmol)文朵灵溶于 20 mL无水四氢呋喃中， 在 0 C冰 浴下緩慢加入 230 mg (6 mmoi)四氢铝锂， 室温下搅拌 4 h后， 加入 0. 23 mL水淬灭反 应；然后依次加入 0.23 mL 15%氢氧化钠和 0,69 mL水，搅拌 5分钟后用砂芯漏斗抽滤， 无水石 酸镁干燥， 减压浓缩， 最后用丙酮重结晶得白色固体化合物 II, 产率 85-90%„
!H NMRfCDC , 300 MHz): 5 8.73(brs, 1H) , 6.82(d, J= 8.1Hz, 1H), 6.24(d, J= 8.1Hz, 1H), 6.06(s， 1H)， 5.80(dd, J= 10.2, 4.8Hz, 1H), 5.60(d, J= 10.2Hz, 1H), 3.93(d5 J= 14.1Hz, 1H), 3,71(s, 3H), 3.54(s, 1H), 2.95(s, 3H)， 2.5 l(s, 1H), 2.43(m, 1H), 2.16(m, 1H)， 1.77(m, 1H), 1.30(m, 1H), 0.86(m, 1H), 0.56(t, J= 8.4Hz, 3H);
13C NMR(CDC13 , 75MHz): δ 160.8(C), 154.5(C), 130.8(CH), 126.4(C), 124.1(CH), 122.7(CH), 104.4(CH), 96.2(CH), 80.7(CH), 77.4(C), 75.1(CH), 68.3(CH), 65.2(CH2), 55.2(OCH3), 51.6(CH2), 51.6(C), 51.2(CH2), 44.7(CH2), 43.6(C), 40.2(CH3), 32.3(CH2), 7.7(CH3);
ESIMS(m/z)387.3 [M+l]+。
1H NMR(CDC13, 300MHz): δ 8.75(brs? 1H), 6.87(d, J= 8.1Hz, 1H), 6.30(d, J= 8.1Hz, 1H), 6.10(s, 1H), 5.88(dd, J= 9.3, 4.8Hz, 1H), 5.61(d, J= 9.3Hz, 1H), 3.87(d5 J- 13.2Hz, 1H), 3.78(s, 3H), 3.61(s, 1H), 2.93(s, 3H), 2.54(s, 1H), 2.43(m, 1H), 2.16(m, 1H), 1.77(m, 1H), 1.30(m, 1H), 0.86(m, 1H), 0.58(t, J= 7.5Hz, 3H);
"C NMR(CDC13, 75顧 z): δ 160.8(C), 154.5(C), 132.1 (CH), 126.4(C), 122.9(CH) 122.9(CH), 104.3(CH), 96.2(CH), 84.6(CH)i 78.4(CH), 75.9(C), 68.3(CH), 55.5(OCH3): 52.6(C), 51.6(CH2), 51.4(CH2), 49.8(CH3), 45.3(CH2), 43.8(C), 41.5(CH3), 32.6(C¾): 7.9(CH3)。 制
取 386 mg C 1 mmol )化合物 II溶于 1 mL 吡啶和 1 mL醋酐混合溶液中， 室温下搅 拌反应 8 h, 然后加入 30 mL乙酸乙酯和 10 mL碳酸氢钠溶液， 继续搅拌 10分钟， 用 水洗去吡啶（ 20 mL X 3 ),将乙酸乙酯层干燥浓缩 ,经硅胶柱层析（石油醚： 丙酮 =6:1 v/v 洗脱）得到化合物 a- 01 (白色粉末）， 产率 78%。
1H NMR (300 MHz, CDC13) 6 9.03 (s, 1H), 6.88 (d, J= 8.2 Hz, IH), 6.31 (dd, J = 8.2, 2.2 Hz, IH), 6.13 (d, J - 2.2 Hz, IH), 5.89 (dd, J = 10.2, 4.8 Hz, IH), 5.37 (d, J = 10.2 Hz, IH), 5.02 (s, IH), 4.19 (d, J- 11.5 Hz, 1H)， 4.02 (d, J = 11.5 Hz, IH), 3.79 (s, 3H), 3.64 (s， IH), 3.46 (dd, J: 16.1, 4.8 Hz, IH), 3.42-3.34(m, 2H), 2.88 (s, 3H), 2.84(s, IH), 2.63(s, IH), 2.50 (q, J = 9.0 Hz, 1H)， 2.39-2.31 (m, 3H)， 2.14 (s， 3H), 2.13 (s, 3H), 2.02-1.99 (m, IH), 1.31-1.25 (m, IH), 1.00—0.94 (m, IH), 0.53 (t, J= 7.3 Hz, IH); ESIMS m/z 470.3 [M+H]+。 制
a-02
将苯并三氮唑 (2 mmol)的 10 mL二氯曱烷溶液水水冷却至 0 °C ,加入 0.32 mL新蒸 三乙胺，搅拌下慢慢滴入对氟苯甲酰氯和酸酑 （2.2 mol)的 2 mL二氯甲梡溶液， 自然升 至室温后继续搅拌反应 2 h。 加水稀释， 用乙酸乙酯萃取 (20 mL x 3), 常规处理蒸干后 得到 N-邻氟苯曱酰基化产物， 不用处理直接进行下步反应。
将化合物 11(1.0 mmol)和 N-酰基笨并三氮唑 BtCOR (1.1 mmol) 溶于 10 mL无水四
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制备方法与制备实施实例 8 中描述的相同， 只是所用酰氯为正戊酰氯以代替丙酰 氯， 产率 71%。
1H NMR (CDC13, 300 MHz) δ 9.23 (brs, 1 H), 6.85 (d, J - 8.1 Hz, 1 H), 6.30 (dd , J = 8.1, 2.1 Hz, 1 H)， 6.16 (d, J - 2.1 Hz, 1 H), 6.11 (d, J- 8.1 Hz, 1 H), 5.87 (dd, J= 10.5, 3.6 Hz, 1 H), 5.37 (d, J: 10.5 Hz, 1 H), 5.01 (s， 1 H), 3.80 (s, 3 H)， 3.79-3.73 (m， 1 H), 3.49 (dd: J = 15.9, 5.1 Hz, 1 H), 3.40 (s, 1 H)， 3.39-3.33 (m, 1 H), 3.04 (d， J= 13.2 Hz, 1 H)， 2.87 (s, 3 H), 2.84 (d, J- 15.9 Hz, 1 H), 2.62 (s， 1 H), 2.57-2.49 (m, 1 H), 2.35-2.17 (m, 3 H), 2.12 (s, 3 H), 2.11 (d， J = 9.9 Hz, 2 H), 1.37-1.28 (m, 1 H), 0.95 (d, J = 6.3 Hz, 6 H), 1.03-0.86 (m， 1 H), 0.52 (t, J= 7.2 Hz, 3 H); ESIMS (m/z) 512.4 [M+l]+。 制备实施
制备方法与制备实施实例 8中描述的相同，只是所用酰氯为环丙基曱酰氯以代替丙 酰氯， 产率 74%。
1H NMR (CDC13, 300 MHz) δ 9.03 (s, 1 H), 6.87 (d, J = 8.1 Hz, 1 H)， 6.32 (dd , J= 8.1, 2.4 Hz, 2 H), 6.15 (d， J = 2.4 Hz, 1 H), 5.90 (d, J= 10.2, 3.6 Hz, 1 H), 5.38 (d, J = 10.2 Hz, 1H), 5.03 (s, 1 H), 3.77 (s, 3 H), 3.76-3.71 (m， 1 H)， 3.52(dd, J = 15.9, 4.5 Hz, 1 H), 3.42 (s, 1 H), 3.41-3.36 (m, 1 H), 3.10 (d, J= 13.5 Hz, 1 H), 2.88 (s, 3 H)， 2.83 (d， J= 15.9 Hz, 1 H)， 2.67 (s, 1 H), 2.57-2.48 (m, 1 H), 2.34-2.21 (m, 2 H ), 2.11 (s, 3 H), 1.44-1.32 (m, 2 H)， 1.18-1.09 (m, 1 H),l.00-0.92 (m, 2H), 0.76-0.68 (m, 2 H), 0.52 (t, J = 7.5 Hz, 3H); ESIMS (m/z) 496.4 [M+l]+。 制备实施实例 13 b-08的制备
! 7
制备方法与制备实施实例 8 中描述的相同， 只是所用酰氯为苯曱酰氯以代替丙酰 氯， 产率 76%。
1H NMR (CDC13, 300 MHz) S 9.27 (brs, 1 H), 7.78 (d, J = 6.9 Hz, 2 H), 7.45 (m, 3 H), 6.92(s, 1 H), 6.89 (d， J= 8.1 Hz, 1 H), 6.35 (d， J= 8.1 Hz, 1 H), 6.17 (s， 1 H), 5.92 (m, 1 H), 5.41 (d, J = 10.5 Hz, 1 H), 5.07 (s, 1 H), 3.94-3.89 (m, 1 H), 3.79 (s, 3 H), 3.55-3.42 (m, 3 H), 3.25 (d, J= 12.9 Hz, 1 H)， 2.91 (s, 3 H), 2.83-2.78 (m, 1 H), 2.70 (s, 1 H), 2.55-2.48 (m, 1 H), 2.25 (m, 1 H), 2.12 (m,3 H), 2.07 (s, 3 H), 1.03 (m, 1 H)， 0.89-0.81 (m, 1 H), 0.53 (t, J = 7.5 Hz, 3 H); ESIMS (m/z) 532.3 [M+l]+。 制备实
制备方法与制备实施实例 8中描述的相同，只是所用酰氯为对氟苯曱酰氯以代替丙 酰氯， 产率 77°/0。
1H NMR (CDC13, 300 MHz) S 9.24 (brs, IH), 7.79 (t, J- 8.1 Hz, 2H), 7.12 (t, J= 8.1 Hz, 2 H), 6.88 (d, J= 8.4 Hz, 1 H), 6.35 (d5 J= 8.4 Hz, 1 H), 6.19 (s, 1 H), 5.91 (dd, J= 10.2, 2.4 Hz, 1 H), 5.42 (d, J = 10.2 Hz, 1 H), 5.06 (s, 1 H), 3.97-3.91 (m, 1 H), 3.79 (s, 3 H), 3.53-3.44 (m, 2 H), 3.43 (s, 1 H), 3.24 (d, J = 13.2 Hz, IH), 2.91 (s, 3 H), 2.86 (d, J = 15.9 Hz, 1 H), 2.72 (s, 1 H), 2.60-2.50 (m, 1 H), 2.32-2.17 (m, 2 H), 2.10 (s, 3 H), 1.37-1.31 (m, 1 H), 1.08-1.00 (m, 1 H), 0.53 (t，J= 7.5 Hz, 3 H); ESIMS (m/z) 550.3 [M+l]+。 制备实施实例 15 b-10的制备
I S
制备方法与制备实施实例 8中描述的相同，只是所用酰氯为邻氟苯曱酰氯以代替丙 酰氯， 产率 73%。
1H NMR (300 MHz, CDC13) δ 9.12 (s, IH), 8.03 (t, J= 7.8 Hz, IH), 7.49—7.39 (m, 2H)5 7.24-7.20 (m, IH), 7.14-7.07 (m, IH), 6.88 (d, J = 8.2 Hz, IH), 6.33 (dd， J = 8.2, 1.6 Hz, IH), 6.18 (d, J= 1.6 Hz, IH), 5.90 (dd, J= 10,4, 4.6 Hz, IH), 5.38 (d? J = 10.4 Hz, IH), 5.04 (s， IH), 4.02 (dd, J= 13.7, 8.0 Hz, 1H)， 3.79 (s, 3H)， 3.47 (s, IH), 3.55-3.35 (m, 2H), 3.26 (d J= 13.6 Hz, IH), 2,92 (s, 3H), 2.83 (d, J= 16.0 Hz, IH), 2.68 (s, IH), 2.53 (dd, J= 17.9, 9.2 Hz, IH), 2.34-2.14 (m, 2H), 2.10 (s, 3H), 1.39-1.25 (m, IH), 1.14-0.93 (m, 1H)， 0.54 (t, J = 12 Hz, 3H); ESI S (m/z) 550.3 [M+l〗+。 制备实施实例 16 b-11的制备
制备方法与制备实施实例 8中描述的相同， 只是所用酰氯为 2,6-二氟苯甲酰氯以代 替丙酰氯， 产率 70%。
1H NMR (400 MHz, CDC13) S 9.33 (s, IH), 7.39-7.29 (m, IH), 6.96-6.85 (m, 3H)S 6.66 (d, J = 8.2 Hz, IH), 6.32 (dd， J 8.2, 2.2 Hz, IH), 6.18 (d5 J = 2.2 Hz, 1H); 5.90 (dd, J = 10.2, 3.8 Hz, IH), 5.39 (d, J= 10.2 Hz, IH), 5.05 (s, IH), 3.99 (q, J = 8.4 Hz, IH), 3.79 (s， 3H), 3.50-3.42 (m, IH), 3.46 (s, IH), 3.38-3.32 (m, IH), 3.22 (d, J- 13.3 Hz, IH), 2.96 (s, 3H), 2.83 (d, J- 15.9 Hz, IH), 2.66 (s, IH), 2.55-2.48 (m, IH), 2.34-2.18 (m, 2H), 2.15 (s, 3H), 1.37-1.26 (m, 1H)， 1.13-0.94 (m, IH), 0.53 (t, J = 7.4 Hz, 3H); ESIMS (m/z) 568.4 [M+l]+。 制备实施实例 17 b-12的制备
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制备方法与制备实施实例 8中描述的相同，只是所用酰氯为对甲氧基苯曱酰氯以代 替丙酰氯， 产率 76%。
1H NMR (CDC13, 300 MHz) S 9.08 (brs, 1 H), 7.23 (d, J- 8.4 Hz, 2 H), 6.88 (d， J= 8.4 Hz, 2 H)， 6.85 (d, J= 8.1 Hz, 1 H), 6.32 (dd， J= 8.1, 2.1 Hz, 1 H)， 6.17 (d, J = 8.1 Hz, 1 H), 6.03 (s, 1 H)， 5.88 (dd, J = 10.2, 3:6 Hz, 1 H), 5.33 (d, J = 10.2 Hz, 1 H); 4.90 (s, 1 H), 3.86-3.80 (m, 1 H), 3.81 (s, 3 H), 3.78 (s， 3 H)， 3.48 (s, 1 H), 3.48-3.40 (m, 1 H), 3.37-3.29 (m, 1 H), 3.16 (s, 1 H), 2.92 (d, J= 13.5 Hz, 1 H), 2.80 (d, J= 15.9 Hz, 1 H); 2.64 (s， 3 H), 2.52-2.43 (m, 1 H), 2.26-2.02 (m, 2 H), 2.09 (s, 3 H), 1.39—1.28 (m? 1 H), 1.03-0.92 (m, 1 H), 0.53 (t, J= 7.2 Hz, 3 H); ESIMS (m/z) 562.3 [M+l „ 制备实施实例 20 b-15的制备
制备方法与制备实施实例 8中描述的相同，只是所用酰氯为间甲氧基苯甲酰氯以代 替丙酰氯， 产率 73%。
1H NMR (300 MHz, CDC13) δ 7.72-7.60 (m, 1H)7.38 (s, IH), 7.31 (s, IH), 7.02 (d, J = 7.4 Hz, IH), 6.95 (d, J= 7.4 Hz, IH), 6.88 (d, J= 8.2 Hz, IH), 6.33 (d, J= 8.2 Hz, IH), 6.17 (s, IH), 5.90 (dd, J= 10.2, 4.7 Hz, IH), 5.39 (d, J= 10.2 Hz, IH), 5.06 (s, IH), 3.94 (dd, J = 13.4, 8.1 Hz, IH), 3.86 (s, IH), 3.84 (s, 3H), 3.79 (s, 3H), 3.55-3.34 (m, 2H), 3.45 (s, IH), 3.25 (d, J= 13.5 Hz, IH), 2.90 (s, 3H), 2.85 (d, J= 16.2 Hz, IH), 2.69 (s, IH), 2.62-2.47 (m, IH), 2.32-2.19 (m, 2H), 2.17 (s, IH), 2.09 (s, 3H), 1.38-1.26 (m, IH), 1.10-0.92 (m, IH), 0.54 (t, J= 7.3 Hz, 3H); ESIMS (m/z) 562.3 [M+l]+。 制备实施实例 21 b-16的制备
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在氩气保护下， 将 2.43 g ( 5 mmol )长春质碱的酒石酸盐和 2.43 g (15 mmol)无水三 氯化铁加入到緩冲溶液中（由 2.76 g(20 mmol)—水合硫酸氢钠和 500 mL 水配制， ρΗ=1.3) , 室温下搅拌 10分钟， 然后加入化合物 a- 01 (5皿 nol)。 室温下搅拌 8 h后， 在 冰浴（O 'C )下滴加入含 400 mg硼氢化钠的氨水溶液 (40 mL) , ；水浴下反应 15-20分钟。 完毕后用二氯曱烷萃取 (200 mL X 4),二氯甲烷层依次经饱和食盐水洗涤（ 200 mL χ 3 )、 硅藻土过滤和低溫减压浓缩得到偶联产物的粗品 IV-a-01。
在氩气的保护下， 将 1.07 g ( 6 mmol )溴代琥珀亚胺， 溶解在 40 mL干燥的二氯曱 烷中， 然后加入 2.13 mL三氟乙酸， 混合均匀待下一步反应。 在氩气的保护下， 将上步 制得的化合物 IV_a-01粗品溶解在 90 mL无水二氯甲烷中并降温至 -70 °C ,然后緩慢滴 加上步制得的溴代反应液， 保持此温度， 加入含有二乙胺为溴代稳定剂的无水二氯曱 烷 20 mL , 继续于此温度下搅拌 1.5 h。 反应结束后， 在体系中立即加入含有四氟棚酸 银的四氢呋喃水溶液 600 mL (四氢呋喃： 水 =1 : 1 )。 逐渐升溫到 50 °C , 避光搅拌反应 3 h。 过滤反应液， 蒸干四氢呋喃， 再用 10%的碳酸钠调节 pH值为 10.0。 二氯甲烷萃 取三次， 合并有机相， 无水硫酸钠干燥， 无水硫酸镁过滤和低温减压浓缩。 将浓缩物 用甲醇重结晶或用硅胶柱层析 (50: 1-100: 1 , CHCl3/MeOH)得到 2.29 g化合物 A-01 (白色 固体)； 最终产率为 58%。 純度经 HPLC检测大于 98%。
1H NMR (400 MHz, CDC13) S 9.25 (brs, IH), 8.46 (s, IH), 7.71 (d, J = 7.7 Hz, IH), 7.15-7.11 (m, 4H), 6.39 (s, IH), 6.13 (s， IH), 5.85 (dd, J= 10.1, 4.0 Hz, IH), 5.71 (d, J= 4.0 Hz, IH), 5.37 (d, J = 10.2 Hz, 1 H)， 4,95 (s, IH), 4.384.26 (m, 2H), 4.17 (d, J = 11.3 Hz, 1H)， 4.12 (J = 1 1.3 Hz, I H), 3.97 (s, IH), 3.82 (s, 3H), 3.67 (s, 3H), 3.57 (s, 1H)， 3.37 (d, J =14.4 Hz, IH), 3.29-3.24 (m, 2H), 3.22-3.13 (m， 3H), 3.09 (s, IH), 2.97 (dd, J = 15.2, 7.4 Hz, IH), 2.88 (s, 3H), 3.37 (d, J =16.4 Hz, IH), 2.62-2.55 (m, IH), 2.48 (s, IH), 2.44-2.29 (m, 3H), 2.15 (s, 3H)， 2.10 (s, 3H), 2.03— 1.96(m, 3H), 1.87-1.83 (m, 2H), 1.43—1.30 (m, IH), 1.20-1.08 (m, IH), 1.04 (t, J = 7.5 Hz, 3H)， 0.70 (t, J = 7.2 Hz, 3H); ESIMS (m/z) 792.5 [M+l]+。
化合物 A-01酒石酸盐的制备： 将上步制得的 2.29 g化合物 A-01溶解在 20 mL丙 酮溶液中，加入含有 1.3 g酒石酸的丙酮溶液 40 mL (酒石酸的摩尔量是 A- 01摩尔量的 3 倍）， 搅拌反应后过滤， 滤液中緩慢加入乙醚 100 mL, 冰浴下析晶， 然后过滤得到 A-01的酒石酸盐 2.76 g (化合物 A-01的酒石酸盐的純度 > 99.5%, HPLC检测 λ 实施例 2
以 a-02替代 a-01， 制备步骤参见化合物 A-01的制备， 得到白色粉末； 最终产率为 62%。
1H NM (400 MHz, CDC13) δ 9.10 (s, IH), 8.51 (s, IH), 8.04-7.88 (m, IH), 7.77 (d, J = 7.8 Hz, IH), 7.53-7.42 (m, IH), 7.21-7.00 (m, 5H), 6.33 (s， 1H)， 6.14 (s, IH), 5.84 (dd, J = 10.2, 4.2 Hz, IH), 5.74 (d, J= 4.2 Hz, IH), 5.37 (d， J= 10.2 Hz, IH), 5.03 (s, IH), 4.58 (d, J = 11.5 Hz, IH), 4.454.30 (m, IH), 4.12 (d, J - 11.5 Hz, IH), 3.95 (s, IH), 3.82 (s, 3H), 3.72 (s, IH), 3.68 (s, 3H), 3.47 (d, J = 14.3 Hz, 1H)， 3.42-3.21 (m, 4H)， 3.15 (s, IH), 3.01 (dd, J= 15.1, 7.8 Hz, IH), 2.96 (s, 3H), 2.68 (d， J= 16.3 Hz, IH), 2.62-2.49 (m, IH), 2.47 (s, IH), 2.40-2.29 (m, IH), 2.16 (s, 3H), 2.10-1.96 (m, 3H)， 1.46-1.35 (m, IH), 1.18-1.09 (m, IH), 1.04 (t, J= 7.5 Hz, 3H), 0.71 (t, J= 7.3 Hz, 3H); ESIMS (m/z) 872.6 [M+l]+„ 化合物 A-03的制备
以 a-03替代 a-01 , 制备步驟参见化合物 A-01的制备， 得到白色粉末； 最终产率为 65%。
!H NMR (400 MHz, CDC13) <5 9.16 (s, IH), 8.55 (s, IH), 8.03 (d, J- 8.9 Hz, IH), 7.83 (s, IH), 7.23-7.14 (m, 3H), 6.92 (d, J= 8.9 Hz, 2H), 6.35 (s, IH), 6.11 (s, IH), 5.88 (dd, J = 10.3, 4.3 Hz, IH), 5.77 (d, J= 4.3 Hz, IH), 5.39 (d, J- 10.3 Hz, IH), 5.08 (s, IH), 4.46 (d，J = 11.5 Hz, IH), 4.14 (d, J = 11.5 Hz, IH), 3.85 (s, 3H), 3.83 (s， 3H), 3.72 (s, 3H), 3.66 (s， IH), 3.38-3.27 (m, 2H), 3.26-3.18 (m, IH), 3.05 (dd, J = 15.9, 7.4 Hz, IH), 2.91 (s, 3H), 2.75 (d，J= 15.9 Hz, IH), 2.64-2.48 (m, 2H), 2.15 (s, 3H), 2.11-2.01 (m, 4H)， 1.90-1.80 (m, 2H), 1.48-1.42 (m, IH), 1.20-1.14 (m, IH), 1.08 (t, J= 7.4 Hz, 3H), 0.73 (t, J= 7.3 Hz, 3H); ESIMS (m/z) 872.6 [M+l]+。 实施例 4 化合物 A-0
A-04 、0
以 a-04替代 a-01， 制备步骤参见化合物 A-01的制备， 得到白色粉末； 最终产率为 62%。
1H NMR (400 MHz, CDC13) δ 9.12 (brs, IH), 8.52 (s, IH), 8.03-7.89 (m, IH), 7,78 (d, J= 7.8 Hz, IH), 7.53-7.42 (m, IH), 7.21-7.02 (m, 5H), 6.34 (s, IH), 6.14 (s, IH), 5.83 (dd, J = 10.2, 4.2 Hz, IH), 5.76 (d, J= 4.2 Hz, IH), 5.38 (d, J= 10.2 Hz, IH), 5.05 (s， IH), 4.59 (d, J = 11.5 Hz, IH), 4.46-4.31 (m, 1H)， 4.14 (d, J = 11.5 Hz, IH), 3.96 (s, IH), 3.83 (s, 3H), 3.73 (s, IH), 3.69 (s, 3H), 3.48 (d, J = 14.3 Hz, IH), 3.43-3.22 (m, 4H), 3.16 (s, IH), 3.02 (dd, J= 15.1, 7.8 Hz, IH), 2.97 (s, 3H), 2.69 (d, J= 16.3 Hz, IH), 2.62-2.50 (m， 1H)， 2.47 (s, IH), 2.40-2.30 (m, IH), 2.17 (s, 3H), 2.12-1.97 (m, 3H), 1.47-1.36 (m, IH), 1.18-1.11 (m， IH), 1.04 (t, J= 7.5 Hz, 3H), 0.73 (t, J= 7.3 Hz, 3H); ESIMS (m/z) 884.6 [M+l]+。 化合物 B- 0
以 b- 01替代 a- 01, 制备步骤参见化合物 A-01的制备， 得到白色粉末； 最终产率 为 63%。
!H NMR (300 MHz, CDC13) δ 9.44 (brs, IH), 8.49 (s, IH), 7.77 (d, J = 8.0 Hz, IH), 7.17-7.10 (m, 3H), 6.31 (s, IH), 6.15 (s, IH), 6.13 (s, 1H)， 5.86 (dd, J - 10.1, 4.4 Hz, IH), 5.74 (d, J= 4.4 Hz, IH), 5.33 (d, J= 10.1 Hz, IH), 4.92 (s, IH), 4.54-4.30 (m, 2H), 3.83 (s, 3H), 3.68 (s, 3H), 3.32-3.24 (m, IH), 3.31 (s, IH), 3.31 (s, IH), 3.18-3.10 (m, IH), 3.06-2.95 (m, 2H), 2.86 (s, 3H), 2.73 (d, J= 16.1 Hz, 1H)， 2.63-2.35 (m, 4H), 2.11 (s, 3H), 2.01 (q, J= 6.9 Hz, 2H)5 1.97 (s, 3H), 1.89-1.78 (m, IH), 1.46-1.32 (m, IH), 1.14-1.07 (m, IH), 1.05 (t, J- 7.4 Hz, 3H), 0.69 (t, J= 7.2 Hz, 3H); ESIMS (m/z) 792.6 [M+l]+。 实施例 6 化合物 B-02的制备
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以 b-05替代 a- 01， 制备步驟参见化合物 A-01的制备， 得到白色粉末； 最终产率 为 64%。
1H NMR (400 MHz, CDC13) δ 9.38 (s, IH), 8.44 (s, IH), 7.72-7.67 (m, IH), 7.19—7.04 (m5 4H), 6.34 (s, IH), 6.17 (d, J- 7.9 Hz, IH), 6.14 (s, IH), 5.84 (dd, J= 10.2, 4.7 Hz, IH), 5.71 (d, J = 4.7 Hz, 1H)， 5.34 (d, J- 10.2 Hz, IH), 4.91 (s, IH), 4.40-4.26 (m, 2H), 3.98 (s, 1H)} 3.81 (s， IH), 3.74 (s, IH), 3.66 (s, 3H), 3.41-3.36 (m, IH), 3.32-3.24 (m, IH), 3.28 (s, IH), 3.22-3.11 (m, 2H), 3.09 (s, IH), 3.02-2.87 (m, 2H), 2.83 (s, 3H), 2.70-2.53 (m, 3H), 2.44 (s, 1H)5 2.43-2.28 (m, 4H), 2.11 (s, 3H)， 2.10 (s, IH), 2.03 - 1,90 (m, 2H), 1.89-1.77 (m， IH), 1.48—1.34 (m, IH), 1.13-1.09 (m, 6H), 1.03 (t, J = 7.4 Hz, 3H); ESIMS (m/z) 820.6
实施例 10 化合物 B-06的制备
以 b-06替代 a-01, 制备步骤参见化合物 A-01的制备， 得到白色粉末； 最终产率 为 66%。
1H NMR (400 MHz, CDC13) S 9.43 (s, IH), 8.46 (s, 1H)， 7.73 (d, J = 7.7 Hz, IH), 7.22-7.05 (m, 3H), 636 (s, IH), 6.16 (s, IH), 6.14 (d，J= 8.4 Hz, IH), 5.86 (dd, J= 10.2, 4.2 Hz, IH), 5.73 (d, J- 4.2 Hz, IH), 5.36 (d, J= 10.2 Hz, IH), 4.94 (s， IH), 4.42-4.29 (m, 2H), 3.83 (s, 3H), 3.80-3.70 (m, 2H)， 3.69 (s, 3H), 3.40 (d, J= 14.1 Hz, 1H)， 3.35-3.27 (m, IH), 3.31 (s, 1H)， 3.24-3.10 (m, 2H), 3.00-2.95 (m, 2H), 2.86 (s, 3H), 2.70 (d, J = 15.8 Hz, IH), 2.60 (dd, J- 15.3, 12.1 Hz, IH), 2.47 (s, IH), 2.45-2.34 (m， 2H), 2.21-2.16 (m, 2H), 2.13 (s, 3H), 2.06-L94 (m， 4H), 1.92-1.81 (m， IH), 1.62-1.55 (m, 2H), 1.46-136 (m, 2H), 1.33-1.29 (m, 2H)， 1.19-1.09 (m, IH), 1.06 (t，J= 7.5 Hz, 3H), 0.89 (dd, J= 9.6, 5.1 Hz, 3H); 0.69 (t， J= 7.4 Hz, 3H); ESIMS (m/z) 833.6 [M+l]+. 实施例 11 化合物
以 b-07替代 a-01， 制备步骤参见化合物 A-01的制备， 得到白色粉末； 最终产率 为 63%。
1H NMR (300 MHz, CDC13) δ 9.42 (s, IH), 8.48 (s， IH), 7.74 (d, J - 7.5 Hz, IH), 7.22-7.08 (m, 3H)， 6.35 (s， IH), 6.31 (d, J= 7.5 Hz, IH), 6.15 (s, IH), 5.86 (dd, J= 10.2, 4.3 Hz, IH), 5.75 (d, J= 4.3 Hz, IH), 5.36 (d, J= 10.2 Hz, IH), 4.94 (s, IH), 4.484.35 (m, IH), 3.83 (s, 3H), 3.68 (s, 3H), 3.48 (d, J - 13.8 Hz, IH), 3.36 (s, IH), 3.34-3.22 (m, 2H), 3.19—3.12 (m, IH), 3.01 (m, IH), 2.86 (s, 3H), 2.72 (d, J- 16.2 Hz, IH), 2.58 (m, 1H)5 2.49 (s, IH), 2.46-2.36 (m, IH), 2.11 (s, 3H)5 2.01 (dd, J= 14.9, 7.6 Hz, 2H); 1.93-1.80 (m, IH), 1.51-1.32 (m, IH), 1.15 (dd, J = 14.3, 7.4 Hz, IH), 1.06 (t, J= 7.4 Hz, 3H), 0.92—0.89 (m, 2H), 0.71-0.66 (m, 5H); ESIMS (m/z) 818.5 [M+l]+。
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以 b-10替代 a-01 , 制备步骤参见化合物 A- 01的制备， 得到白色粉末； 最终产率 为 68%。
1H NMR (400 MHz, CDC13) S 9.31 (brs, IH), 8.46 (s, IH), 8.03 (td, J= 7.8, 1.7 Hz, 1H): 7.72 (s, IH), 7.60-7.38 (m, 2H), 7.25-7.07 (m, 6H), 6.40 (s, IH), 6.20 (s, IH), 5.88 (dd, J = 10.2, 4.6 Hz, IH), 5.73 (d, J= 4.6 Hz, IH), 5.38 (d, J= 10.2 Hz, IH), 5.00 (s, IH), 4.40-4.25 (m， IH), 3.98 (s, IH), 3.85 (s, 3H), 3.75 (s, IH), 3.71 (s, 3H), 3.41 (s, 3H), 3.39-3.29 (m, 2H); 3.26-3.16 (m, 3H), 3.13 (s, IH), 2.93 (s, 3H), 2.79-2.57 (m， 2H), 2.49 (s, IH), 2.14 (s， 3H), 2.05-1.94 (m, 3H), 1.91-1.80 (m， H), 1.48-1.37 (m， IH), 1.23-1.13 (m5 1H)， 1.06 (t, J= 7.5 Hz, 3H)， 0.69 (t, J= 7.3 Hz, 3H); 13C NMR (CDC13, 101 MHz) 6 174.9, 170.7, 163.3, 160.4, 158.0, 153.2, 135.7, 134.4， 133.4, 132.9, 131.6, 129.9, 128.9, 124.6, 124.5, 123.6, 123.3, 122.5, 121.5, 120.9, 119.6, 118.2, 116.0, 115.8, 110.3, 94.9, 82.5, 77.3, 77.2, 77.0, 76,7， 75.7, 65.2, 55.6, 55.2, 54.9, 52.6, 50.2, 49.9, 47.1, 44.9， 43.6, 42.6, 41.1, 35.9, 30.9， 29.0, 27.9, 20.9, 12.2, 7.9; ESIMS (m/z) 872.5 [M+lf„ 实施例 15
以 b-11替代 a-01 , 制备步骤参见化合物 A-01的制备，得到白色粉末； 最终产率为
59%。
'H NMR (400 MHz, CDC13) δ 9.56 (s， IH), 8.50 (s, IH), 7.76-7.67 (m, 2H), 7.51 (dd, J = 5.7, 3.3 Hz, IH), 7.3 7,29 (m, IH), 7.18-7.11 (m, 3H), 6.93-6.89 (m, 2H), 6.67 (d, J - 8.1 Hz, IH), 6.35 (s， IH), 6.19 (s, 1H)， 5.87 (dd, J= 10.2, 4.6 Hz, IH), 5.75 (d, J= 4.6 Hz, IH), 5.38 (d, J- 10.2 Hz, IH), 4.98 (s, IH), 4.48-4.38 (m, 2H), 4.29 (t, J= 6.7 Hz, IH), 3.96 (s, IH), 3.92-3.87 (m, 1H)， 3.84 (s, 3H), 3.73 (s, IH), 3.69 (s, 3H), 3.42-3.38 (m， 4H), 3.36-3.33 (m, 4H), 3.18-3.11 (m, 3H), 3.02 (dd, J= 14.7, 6.9 Hz, IH), 2.97 (s, 3H), 2.83 (q, J - 7.2 Hz, 2H), 2.72 (d, J = 16.3 Hz, IH), 2.61-2.54 (m, IH), 2.51 (s, 1H)， 2.47-2.36 (m, 3H), 2.17 (s, 3H), 2.05-1.92 (m, 4H), 1.90-1.79 (m, IH), 1.47-1.39 (m, IH), 1.26-1.22 (m， IH), 1.20—1.14 (m, IH), 0.94 (t, J = 7.4 Hz, 3H), 0.70 (t, J = 7.3 Hz, 3H); ESIMS (m/z) 890.5 [M+l]+。
实施例 16
以 b-12替代 a-01, 制备步骤参见化合物 A-01的制备， 得到白色粉末； 最终产率 为 67%。
Ή NMR (400 MHz, CDC13) δ 9.56 (s, IH), 8.51 (s, IH), 7.75 (d, J= 7.6 Hz, IH), 7.71 (d， J = 8.5 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.18-7.11 (m, 3H), 6.91 (d, J = 7.3 Hz, IH), 6.41 (s, IH), 6.17 (s, IH), 5.88 (dd, J= 10.4, 4.4 Hz, IH), 5.74 (d, J= 4.4 Hz, IH), 5.38 (d， J = 10.4 Hz, IH), 4.99 (s, IH), 4.534.27 (m, 2H), 3.98-3.85 (m, IH), 3.83 (s, 3H), 3.70 (s, 3H), 3.48 (d, J- 13.9 Hz, IH), 3.36 (s, IH), 3.33-3.29 (m, 2H), 3.21-3.14 (m; 2H), 3.00 (dd, J = 15.5, 7.6 Hz, IH), 2.89 (s, 3H), 2.74 (d, J = 15.8 Hz, IH), 2.57 (s， IH), 2.51-2.37 (m, 2H), 2.10 (s, 3H), 2.05-1.93 (m, 4H), 1.92—1.81 (m, IH), 1.48—1.34 (m; IH), 1.22-1.12 (m, 1H)， 1.05 (t, J= 7.4 Hz, 3H), 0.70 (t, J= 7.3 Hz, 3H); ESIMS (m/z) 887.6 [M+l]+。
Ή NM (400 MHz, CDCI3) δ 9.31 (brs, IH), 8.49 (s, IH), 8.47 (s, IH), 8.13 (dd, J = 8.1, 1.8 Hz, 1H)， 7.74 (d， J= 8.1 Hz, IH), 7.44-7.37 (m, IH), 7.20-7.12 (m, 3H), 7.04 (t, J= 7.6 Hz, IH), 6.95 (d, J= 8.3 Hz, IH), 6.34 (s, IH), 6.15 (s, IH), 5.87 (dd, J = 10.1, 4.6 Hz, IH), 5.73 (d, J= 4.6 Hz, IH), 5.38 (d, J= 10.1 Hz, IH), 5.00 (s， IH), 4.38 (s, IH), 3,97—3.88 (m, IH), 3.91 (s, 3H), 3.83 (s, 3H), 3.69 (s, 3H), 3.41 (s, IH), 3.33 (dd, J= 16.0， 4.6 Hz, IH), 3.27-3.11 (m, 3H), 3.00 (dd, J = 15.5, 7.5 Hz, 1H)， 2.89 (s, 3H), 2.72 (d, J = 16.1 Hz, IH), 2.59 (dd, J = 15.2， 12.2 Hz, IH), 2.49 (s, IH), 2.48-2.32 (m, 2H), 2.11 (s, 3H)， 2.00 (q, J = 7.0 Hz, 2H), H1.80 (ra, IH), 1.50-1.35 (m, IH), 1.27-1.11 (m, IH), 1.05 (t, J = 7.5 Hz, 3H), 0.74-0.67 (m, 3H); ESIMS (m/z) 884.6 [M+l]+。 实施例
以 b-14替代 a-01, 制备步骤参见化合物 A-01的制备， 得到白色粉末； 最终产率 为 65%。
lH NMR (400 MHz, CDC13) δ 9.46 (brs, 1H)} 8.48 (s, IH), 7.83-7.67 (m, 3H), 7.20-7.08 (m， 2H), 7.28― 7.06 (m, 3H), 6.96-6.86 (m， 3H), 6.83 (d, J= 7.6 Hz, IH), 6.38 (s， IH), 6.16 (s, IH), 5.88 (dd, J = 10.2， 4.1 Hz, IH), 5.73 (d, J= 4.1 Hz, IH), 5.39 (d, J= 10.2 Hz, IH), 5.00 (s, IH), 4,38-4.33 (m, 2H), 3.94-3.85 (m, 2H), 3.83 (s, 3H), 3.82 (s， 3H), 3.76 (s, IH), 3.70 (s, 3H), 3.45-3.39 (m, IH), 3.39 (s, IH), 3.33 (dd, J = 16.4, 4.8 Hz, IH), 3.27-3.13 (m, 4H), 2.98 (dd, J = 15,5, 7.5 Hz, IH), 2.89 (s, 3H)， 2.72 (d, J- 16.6 Hz, IH), 2.62-2.57 (m, IH), 2.50 (s, IH), 2.46― 2.34 (m, 2H); 2.11 (s, 3H), 2.05-1.95 (m, 4H), 1.91-1.80 (m， IH), 1.48-1.36 (m, 1H)， 1.25-1.11 (m, IH), 1.05 (t, J= 7.5 Hz, 3H), 0.70 (t, J - 7.3 Hz, 3H); 13C NMR (CDC13， 100 MHz) δ 175.2, 170.8, 167.0, 161.9, 157.8, 153.1, 134.6, 134.0, 130.2, 128.8, 128.6, 126.8, 124.5, 124.3, 123.6, 123.5, 122.0, 120.4, 118.9,
117.7, 113.5, 110.6, 94.4, 82.4, 77.3, 77.2, 77.0, 76.9, 76.7, 76.0, 63.9, 55.5, 55.2, 54.9, 53.9， 52.7, 52.6, 50.1, 49.5, 46.1, 45.0， 43.3， 43.2, 42.6, 40.7, 35.7, 30.9， 28.6, 27.8, 20.8, 12.1, 7.7; ESIMS (m/z) 884.5 [M+l]+。 实施例
Ή NMR (400 MHz, CDC13) δ 9.36 (brs, 1H)， 8.53 (s, IH), 7.79-7.76 (m, IH), 7.37-7.28 (ra, 3H), 7.21-7.12 (m, 3H), 7.06-6.99 (m, IH), 6.93 (d, J= 8.0 Hz, IH), 6.38 (s, 1H)， 6.18 (s, 1H)， 5.88 (dd, J= 10,2, 4.4 Hz, IH), 5.75 (d, J= 4.4 Hz, 1H)， 5.39 (d, J= 10.2 Hz, IH), 4.99 (s, IH), 4.60 (d, J = 13.1 Hz, IH), 4.40 (d, J = 13.2 Hz, IH), 3.88 (m, IH), 3.84 (s, 3H), 3.82 (s, 3H), 3.70 (s, 3H), 3.52 (d, J= 11.0 Hz, IH), 338 (s, IH), 3.35-3.29 (m, 2H), 3.22-3.15 (m, 2H), 3.04 (dd, J = 15.8, 7.3 Hz, IH), 2.90 (s, 3H), 2.79 (d， J = 16.0 Hz, IH), 2.58 (s, IH), 2.55-2.45 (m, 2H)， 2.12 (s, 3H), 2.02 (q, J = 6.8 Hz, 2H), 1.92-1.81 (m， IH), 1.44-1.39 (m, IH), 1.20-1.14 (m, IH), 1.06 (t, J - 7.5 Hz, 7H), 0.72 (t, J = 7.3 Hz, 3H); ,3C NMR (CDC13, 100 MHz) δ 174.5, 170.7, 167.2, 159.7, 158.0, 153.5, 136.1, 134.4, 134.0, 129.8, 129.4, 128.6, 124.8, 123.6, 123.4, 123.1, 120.3, 118.6, 118.5, 117.2, 112.4, 110.4, 94.7, 82.1, 77.3, 77.2, 77.0, 76.9, 76.7, 75.9, 65.0, 55.6, 55.3, 54.6, 53.8, 52.8, 52.6, 50.0, 49.7， 46.7, 44.9, 44.0, 43.3, 42.7, 40.7, 35.2, 31.8, 30.9， 29.6, 29.3, 28.3, 27.6, 22.6, 20.9, 14.0， 12.0, 8.0; ESIMS (m/z) 884.5 [M+l]+。 实施例 20 化合物 B-16的制备
以 b-16替代 制备步 参见化合物 A-01的制备， 得到白色粉末； 最终产率 为 65%。
1H NMR (400 MHz, CDC13) δ 9.45 (s, IH), 8.48 (s, IH), 7.72 (d, J= 7.7 Hz, 1H)， 7.43 (d, J = 1.8 Hz, IH), 7.29 (dd, J - 83, 1.8 Hz, IH), 7.17-7.12 (m, 3H), 6.89-6.80 (m, 2H), 6.41 (s, IH), 6.18 (s, IH), 5.88 (dd, J- 10.3, 4.5 Hz, IH), 5.72 (d, J= 4,5 Hz, IH), 5.40 (d, J = 10.3 Hz, IH), 5.27 (s, IH), 5.02 (s, IH), 4.36 (d, J = 12.8 Hz, IH), 4.28 (d, J= 12.8 Hz, IH), 3.91 (s, 3H), 3.89 (s, 3H), 3.84 (s, 3H), 3.69 (s, 3H), 3.39 (s, IH), 3.42-3.30 (m, 2H), 3.23-3.14 (m, 3H), 2.98 (dd, J = 15.4， 7.4 Hz, IH), 2.91 (s, 3H), 2.70 (d, J = 15.7 Hz, 1H)5 2.65-2.55 (m, IH), 2.51 (s, IH), 2.43-2.34 (m， 2H), 2.12 (s, 3H)5 2.03-1.94 (m, 3H), 1.92-1.83 (m, 2H), 1.49-1.39 (m, IH), 1.21-1.13 (m, IH), 1.05 (t, J= 7.4 Hz; 3H), 0.71 (t，J = 7.3 Hz, 3H); ESIMS (m/z) 914.5 [M+l]+。 实施例 21 化合物 Β-Π的制备
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以 b-19替代 a- 01， 制备步骤参见化合物 A-01的制备， 得到白色粉末； 最终产率 为 65%。
Ή NM (400 MHz, CDC13) S 9.41 (s, IH), 8.47 (s, IH), 7.73 (d, J= 7.7 Hz, IH), 7.45 (s, IH), 7.21-7.12 (m, 3H), 7.09 (d, J = 3.4 Hz, IH), 7.05 (d, J = 7.7 Hz, 1H)， 6.49 (dd, J = 3.4, 1.7 Hz, 1H)， 6.41 (s, IH), 6.19 (s, IH), 5.89 (dd, J - 10.2, 4.1 Hz, IH), 5.74 (d, J = 4.1 Hz, IH), 5.41 (d, J= 10.2 Hz, 1H)， 5.02 (s, IH), 4.38 (d, J = 12.6 Hz, IH), 4.28 (d, J= 12.5 Hz, 1H)， 3.94-3.88 (m, IH), 3.86 (s, 3H), 3.71 (s, 3H), 3.40 (s, IH), 3.40 (s, IH), 3.42-3.31 (m, 2H), 3.27-3.12 (m, 3H), 3.03-2.93 (m, IH), 2.94 (s, 3H)， 2.70 (d，J= 16.1 Hz, 1H)， 2.64 (dd, J = 15.2, 12.2 Hz, IH), 2.48 (s, IH), 2.44-2.29 (m， 2H), 2.18 (s, IH), 2.14 (s, 3H), 2.06-1.97 (m， 3H), 1.9^1.82 (m, IH), 1.44 (dq, J : 14.6, 7.1 Hz, IH), 1.25-1.13 (m, IH), 1.07 (t，J= 7.5 Hz, 3H); 0.72 (t, J= 7.1 Hz, 3H); 13C NMR (100 MHz, CDC13) S 174.9, 170,6: 158.5, 158.1, 153.3, 148.1, 143.8, 135.8, 134.5, 133.5, 129.9, 128.9， 124.6, 123.7, 123.4, 123.2, 122.5, 120.7, 119.6, 118.3, 113.7, 111.9, 110.3, 94.7, 82.7, 77.2, 75.9, 65.5, 55,6, 55.2, 54.9, 53.4, 52.6, 52.6, 50.3, 50.0, 47.1, 44.9, 44.8, 42.8， 42.7, 40.8, 35.9, 30.9, 29.1, 27.9, 20.8, 12.2, 7.9; ESIMS (m/z) 845.5 [M+l]+。
以上述长春瑞滨衍生物的制备例做参考， 结合本领域现有技术， 其他的长春瑞滨 衍生物及其生理上可接受的盆也可如法制备。 试臉实施例
试验实施例 1 本发明化合物的体外抗肿瘤活性实验
试剂材料：
细胞株： A549人非小细胞肺癌细胞株（购自 ATCC )
阳性对照药： 长春瑞滨酒石酸盐（按常规方法配制）； 纯度由 HPLC-UV检测 98 % 以上， 结构由 NMR确证。 受试化合物和阳性对照物以生理盐水稀释， 浓度梯度为 1CT4 M、 IO-5 M、 10— 6 Μ、 1(Γ7 Μ、 10"8 Μ„
实验方法：
采用 MTS方法： 化合物对细胞作用一段时间后， 采用 MTS方法检测细胞存活状 态。 原理与 MTT法的原理是一致的， 区别是 MTS检测试剂盒（Promega, cat#G5421) 中的成分与细胞作用后， 形成的是可溶性的甲贊， 在 490nm下有最大吸收。 这种方法 的优势在于并不杀死细胞，在不去除培养基的状况下能时时进行检测。通过检测 490mn 下的吸光度值计算出细胞存活率。
实验步骤：
A549细胞体外培养，培养基为 RPMI-1640,含 10%FBS , 2 mM谷氣酰胺 ， 10 mM HEPES, 0.11g/L 丙酮酸钠， l x l05U/L青霉素， 1 χ 10 g/L链霉素。 收集处于对数生 长期的细胞， 经台盼蓝检测细胞活力后， 接种于 96孔微量培养板内。 贴壁生长过夜， 再加入 50 μΐ舍不同浓度化合物的培养基， 每孔终体积为 150 μ1。 在 37 。C、 5%C02条 件下培养 48-72小时，加 MTs液 30 μΐ/孔，继续培养 1-4小时。 多功能酶标仪（ Molecular device SpectraMax M5 )检测 OD490。按下列公式计算被测物对肿瘤细胞生长的抑制率， 半数抑制量 IC50值采用 Logit法计算。 抑制率 = (对照组 OD值 -给药组 OD值） /对照 组 OD值 X 100%。
测定结果： 表 1、 对 A- 549人肺癌细胞株细胞增殖抑制活性
(用于评价的样品全部是相应的酒石酸盐）
化合物 A549 ( IC50, nM )
长春瑞滨酒石酸盐 9.0
A-01 23.2
A-02 12.1
A-03 12.6
A- 04 14.3
B-01 34.5
B-02 16.3
B-03 18.6
B-04 17.3
B-05 11.1
B-06 20.6
B-07 3.0
B-08 5.1
B-09 7.0
B-10 7.3
B-11 7.9
B-12 25.5
B-13 6.1
B- 14 6.7
B-15 7.6
B-16 15.6
B-17 6.6
B-18 5.2
B-19 3.2 如表 1 所示， 细胞水平上的筛选结果很明显的显示本发明的长春瑞滨衍生物具有 抑制肿瘤细胞抹的增殖活性。 并且有数个长春瑞滨衍生物的抑制肿瘤细胞株的增殖活 性强于阳性对照长春瑞滨 （NVB )。 试验实施例 2 对 A549棵鼠移植瘤模型的体内抗肿瘤活性评价
试剂材料：
细胞株： A549人非小细胞肺癌细胞株（购自 ATCC )„
试验动物： Balb/C棵鼠， 雄性， 6周龄， 购自北京华阜康生物科技股份有限公司。 饵养于 SPF环境， 温度 20~25 'C , 相对湿度 40~70%, 12: 12h光暗照明； 自由饮水及 采食。 长春瑞滨及受试药物（B-08， B-19 ) 均采用合成方法制备而得， 纯度 >98%。
实验方法：
A549细胞在体外培养扩增， 收取对数生长期细胞， 重悬于无血清 F-12K培养液中 接种于裸鼠右前肢腋窝皮下； 22天后， 肿瘤生长至约 260 mm3, 才艮据肿瘤大小采用随 机区组法将荷瘤鼠分组（6只/组）， 包括溶剂对照组， 阳性对照长春瑞滨（NVB )组， 及受试样品组。 静脉注射（iv )给药， 给药一次， 观测肿瘤生长情况。
测定结果：
B-08和 B-19对 A549棵鼠移植瘤均显示一定抑制作用， 在相同剂量， B-19的抗肿 瘤活性高于 NVB„ 试验实施例 3 对 MDA-MB- 231棵鼠移植瘤模型的体内抗肿瘤活性评价
试剂材料：
细胞株： 人乳腺癌 MDA-MB-231， 来自中国科学院细胞库。
试验动物： Balb/C棵鼠， 雌性， 6周龄， 购自北京华阜康生物科技股份有限公司。 词养于 SPF环境， 温度 20~25 °C , 相对湿度 40~70%, 12: 12h光暗照明； 自由饮水及 采食。 长春瑞滨及受试药物（B-14 ) 均采用合成方法制备而得， 纯度 >98%。
实验方法：
MDA-MB-231细胞在体外培养扩增，收取对数生长期细胞，重悬于 DMEM无血清 培养液后接种于棵鼠右前肢腋窝皮下； 14天后， 肿瘤生长至约 250 mm3; 根据肿瘤大 小采用随机区组法将荷瘤鼠分为组， 溶剂对照組尾静脉注射生理盐水注射液， 每周 1 次； 阳性对照 NVB和受试药物 B-14尾静脉注射给药（iv ), 每周 1次， 连续 21天， 观 测肿瘤生长情况。
测定结杲：
B-14对 MDA- MB- 231棵鼠移植瘤显示一定抑制作用， 在相同剂量， NVB抗肿瘤
活性不明显。 试验实施例 4 本发明化合物的稳定性试验
样品制备：
精密称取中国专利申请 CN200710036923.2中公开的如下结构式所示化合物 7、 34、 38和《的酒石酸盐（以上化合物按照 CN200710036923.2中公开的方法事先制备）， 以 及以上制备的本发明化合物 A-01、 B-07、 B-17和 B-19的酒石酸盐各 10 mg, 分别置 10 ml量瓶中， 加蒸偬水溶解， 加流动相至刻度， 摇匀， 即得（每 1 ml中含各待测化合 物 °C的容器里储存。
分别精密吸取以上制备的溶液各 10 μΐ,检测 0、 6小时样品峰面积的变化考察样品 的稳定性。 样品在 0小时的纯度设为 100%, 6小时的样品峰面积除以 0小时的样品峰 面积为样品在 6小时的純度。
色谱条件：
以十八垸基硅烷键合硅胶为填充剂； 以乙腈-水 ( 50 mM KH2P04 + 5 mM 十二烷基 酸钠）（50:50) 为流动相； 流速为 1 ml/min; 检测波长 266 nm; 柱温为 40。C。
表 2、 CN200710036923.2中公开的化合物
与本发明化合物酒石酸盐在水溶液中的稳定性结果对比
Claims
1. 具有式 I所示结构的长
R2为 0 或 NR4R5; 其中 为 ^1、 CrC6烷酰基或芳香酰基， R4、 R5各自独立地 为 d-C6烷酰基、 C3-C6环烷酰基、 芳香酰基或 CrC6杂芳香酰基； R3、 、 R5中所 迷芳香酰基中的芳香基为苯基或者被 1-4个选自由卤素、 甲基、三氟甲基和曱氧基所组 成组中的基团取代的苯基， 且所述 C3-C6杂芳香酰基中的杂原子是 1-3个选自由 0、 S 和 N所组成组中的原子。
2.根据权利要求 1所述的长春瑞滨衍生物或其可药用的盐， 其中 Rt为乙酰基， R2 为乙酸酯基、 对氟苯曱酸酯基、 邻氟苯曱酸酯基、 对曱氧基苯曱酸酯基、 乙酰胺基、 丙酰胺基、 丁酰胺基、 异丁酰胺基、 戊酰胺基、 环丙曱酰胺基、 苯曱酰胺基、 对氟苯 曱酰胺基、 邻氟苯曱酰胺基、 2,6-二氣苯曱酰胺基、 对氯苯曱酰胺基、 邻甲氧基苯甲酰 胺基、 对曱氧基苯曱酰胺基、 间甲氧基苯曱酰胺基、 3，4-二曱氧基苯曱酰胺基、 对曱基 苯曱酰胺基、 对三氟曱基苯甲酰胺基或者糠酰胺基。
3.根据权利要求 1所述的长春瑞滨衍生物或其可药用的盐， 其中 为丙酰基， 为丙酰胺基。
4.根据权利要求 1-3中任意一项所述的长春瑞滨衍生物或其可药用的盐，其中所述 可药用的盐为所迷长春瑞滨衍生物与酸加成得到的盐或与碱加成得到的盐， 所述酸为 盐酸、 硫酸、 磷酸、 乙酸、 柠檬酸、 草酸、 丙二酸、 水枥酸、 苹果酸、 富马酸、 琥珀 酸、 抗坏血酸、 马来酸、 酒石酸、 甲磺酸或羟乙橫酸； 所述碱为碳酸钠、 碳酸钾、 氢 氧化钠、 氢氧化钾、 、 三乙胺或三乙醇胺。
5. —种药物组合物，含有治疗有效量的选自根据权利要求 1-4中任一项所述的长春 瑞滨衍生物和其可药用的盐中的一种或多种作为活性成分。
6. 根据权利要求 1-4 中任意一项所述的长春瑞滨衍生物或其可药用的盐在制备治 疗恶性肿瘤的药物中的应用。
7.根据权利要求 6所述的应用， 其中所述恶性肿瘤为肺癌、 乳腺癌、 肝癌、 胃癌、 食道癌、 结肠癌、 白血病、 淋巴癌、 前列腺癌、 肾癌、 皮肤癌、 胰腺癌、 卵巢癌、 脑 癌、 骨髓癌或纤维肉瘤。
8. 一种根据权利要求 1-4 中任意一项所述的长春瑞滨衍生物或其可药用的盐的制 备方法， 包括如下步骤：
a.
VI 目标化合物 a、 式 II所示化合物经酰化和 /或酰胺化得到式 III所示中间化合物；
b、 式 III所示中间化合物与长春质碱在緩冲溶液中偶合得到中间产物 VI； 和 c、 中间产物 VI经缩环得到所述长春瑞滨^"生物；
其中 为 ^-^烷酰基；
为 0 或 NR4R5; 其中 为 11、 d-C6烷酰基或芳香酰基， 、 R5各自独立地 为 d-C6烷酰基、 C3-C6环烷酰基、 芳香酰基或 C3-C6杂芳香跣基； R3、 、 中芳 香基为苯基或者被 1-4个选自由卤素、 甲基、 三氟甲基和曱氧基所组成组中的基团取代 的苯基， 所述 C3-C6杂芳基中的杂原子是 1-3个选自由 0、 S和 N所组成组中的原子。
9. 根据权利要求 8所述的制备方法，其中步骤 a中酰化的溶剂为二氯曱烷、氯仿或 四氢呋喃。
10.根据权利要求 8所述的制备方法，其中步骒 a中酰化的碱化反应试剂为氢化钠、 吡啶或者 33%的乙酸钠水溶液。
11.根据权利要求 8所述的制备方法， 其中步骤 a中酰化的酰化剂为酸酐、 酰氯或
酰氯与苯并三氮唑形成的配体。
12， 居权利要求 8所述的制备方法， 其中步骤 a的反应温度为 0 'C至室温。
13. 根据权利要求 8所述的制备方法， 其中步骤 b偶合所用的緩冲溶液为 4¾酸氢钠 水溶液。
14.根据权利要求 13所述的制备方法， 所述緩冲溶液的 pH为 1.3。
15.根据权利要求 8所述的制备方法， 其中步骤 c是中间产物 VI在溴代反应液中 溴代， 然后在四氢呋喃水溶液中通过缩环试剂四氟硼酸^^而进行所述缩环。
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Non-Patent Citations (8)
| Title |
|---|
| HU, L. J. ET AL.: "Synthesis and structure-activity relationship studies of cytotoxic vinorelbine amide analogues", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, no. 24, 17 October 2012 (2012-10-17), pages 7547 - 7550 * |
| LI, W. H. ET AL.: "BM6, a new semi-synthetic Vinca alkaloid, exhibits its potent in vivo anti-tumor activities via its high binding affinity for tubulin and improved pharmacokinetic profiles", CANCER BIOLOGY & THERAPY, vol. 6, no. 5, May 2007 (2007-05-01), pages 787 - 794 * |
| SHAO, Y. ET AL.: "Synthesis and structure-activity relationship studies of cytotoxic anhydrovinblastine amide derivatives", JOURNAL OF NATURAL PRODUCTS, vol. 72, no. 6, 5 June 2009 (2009-06-05), pages 1170 - 1177 * |
| SHAO, Y. ET AL.: "Synthesis and structure-activity relationships study of novel anti-tumor carbamate anhydrovinblastine analogues", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 15, no. 15, 23 May 2007 (2007-05-23), pages 5061 - 5075 * |
| SONG, W. B. ET AL.: "Ceric ammonium nitrate-promoted oxidative coupling reaction for the synthesis and evaluation of a series of anti-tumor amide anhydrovinblastine analogs.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS., vol. 22, no. 1, 6 November 2011 (2011-11-06), pages 387 - 390 * |
| SONG, W. B. ET AL.: "The effect of vindoline C-16 substituents on the biomimetic coupling reaction: Synthesis and cytotoxicity evaluation of the corresponding vinorelbine analogues", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, no. 10, 29 March 2012 (2012-03-29), pages 3485 - 3487 * |
| ZAVALA, F. ET AL.: "Interaction of vinblastine analogs with tubulin", EXPERIENTIA, vol. 34, no. 11, 15 November 1978 (1978-11-15), pages 1497 - 1499 * |
| ZHANG, H. K. ET AL.: "Synthesis and structure-activity relationship studies of cytotoxic ester and ether anhydrovinblastine derivatives", JOURNAL OF NATURAL PRODUCTS, vol. 71, no. 10, 4 September 2008 (2008-09-04), pages 1669 - 1676 * |
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