WO2009036656A1 - Coumarin derivatives, preparation processes and uses thereof - Google Patents
Coumarin derivatives, preparation processes and uses thereof Download PDFInfo
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- WO2009036656A1 WO2009036656A1 PCT/CN2008/070118 CN2008070118W WO2009036656A1 WO 2009036656 A1 WO2009036656 A1 WO 2009036656A1 CN 2008070118 W CN2008070118 W CN 2008070118W WO 2009036656 A1 WO2009036656 A1 WO 2009036656A1
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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- the present invention relates to a coumarin derivative, a process for its preparation and the use as an angiogenesis inhibitor for the treatment of tumors and vascular retinopathy.
- Tumor growth, metastasis, recurrence, and prognosis are closely related to angiogenesis.
- Targeting tumor angiogenesis can greatly improve the therapeutic effect of solid tumors.
- the angiogenesis inhibitory effect is almost the same vascular endothelial cells in different tumor tissues.
- This tumor vascular endothelial cells have no significant difference compared with normal endothelial cells except for the rapid proliferation rate.
- Normal endothelial cells have a long life span and a stable genotype.
- endothelial cells are one of the longest-lived cells in the body. The endothelial cells present on the wall of adult blood vessels were only about 0.01% in the split state at the same time.
- angiogenesis inhibitors The proliferation rate of tumor vascular endothelial cells was about 50 times higher than that of normal tissues. Therefore, the use of angiogenesis inhibitors has a relatively specific effect on tumor blood vessels, but does not significantly affect blood vessels in normal tissues.
- endostatin and angiostatin are currently known as strong endogenous angiogenesis inhibitors, the production of such high-purity safe preparations requires high technical thresholds and the effects of these active proteins on short half-lives in vivo. This limits the clinical application of these active proteins. Therefore, the search for angiogenesis inhibitors in small molecule compounds has become the focus of research.
- Combretastatin A-4 is a stilbene compound with antitumor activity isolated from the trunk of Combretum caffrum in South Africa (US Patent 4996237, Feb, 22, 1988). Due to the poor solubility of this compound, phosphorylation of the prodrug combertastatin A-4 sodium phosphate (CA4P) (US Patent 5,561,122, Dec, 22, 1994), its anti-tumor activity is greatly improved, CA4P rapidly dephosphorylates in vivo to form CA4 The plasma half-life is 30 min. CA4 acts directly on endothelial cells to induce proliferation of proliferating endothelial cells, thereby inhibiting angiogenesis.
- CA4P phosphorylation of the prodrug combertastatin A-4 sodium phosphate
- CA4P has not only made progress in the study of solid tumors, but also made breakthroughs in the treatment of abnormal angiogenesis in various ophthalmic diseases. Especially in the treatment of patients with advanced diabetes, visual blur and blindness caused by vascular retinopathy may become A new drug for the treatment of vascular proliferative retinopathy.
- Combrastastatin A-4 Osthol is a coumarin compound extracted from the Chinese medicine Cnidium. In recent years, studies have shown that osthole can inhibit the growth of lung adenocarcinoma and lung squamous cell carcinoma to varying degrees. The aqueous extract of Cnidium can significantly inhibit the growth of S180 sarcoma in Kunming mice.
- osthole has a significant inhibitory effect on EVC-304, but it is weaker than CA4. Structural modification on the structure of osthole, maintaining the basic structure of coumarin, and introducing a stilbene functional group to obtain a series of derivatives. 5 ⁇ 10 ⁇ The coumarin derivative EVC-304 inhibition is CA. Summary of the invention
- Another object of the present invention is to provide a process for preparing a coumarin derivative.
- a further object of the present invention is to provide the use of the above compound or a pharmaceutically acceptable salt thereof as an angiogenesis inhibitor for the preparation of a therapeutic antitumor drug.
- a further object of the present invention is to provide the use of the above compound or a pharmaceutically acceptable salt thereof as an angiogenesis inhibitor for the preparation of a medicament for treating vascular retinopathy.
- the object of the present invention can be achieved by the following measures:
- the coumarin derivative of the present invention is represented by the following formula (I), which is obtained by modifying the structure of osthole.
- the invention can also be obtained by the following method:
- R1, R2, R3, R4 or R5 represents hydrogen, amino or substituted amino, fluorenyl or substituted fluorenyl or OM, respectively, wherein M is hydrogen, fluorenyl or substituted fluorenyl or phosphoric acid and salts thereof.
- M is hydrogen, fluorenyl or substituted fluorenyl or phosphoric acid and salts thereof.
- the starting materials for the preparation of the compounds 15 to 24 can be obtained by the following methods.
- MTT dimethylthiazole diphenyltetrazolium bromide test EVC-304 cells in logarithmic growth phase, digested with 0.25% trypsin for 3 ⁇ 5min, terminate digestion with medium, adjust cell concentration 5 X 10 4 /mL , inoculate 150 ⁇ /well in 96-well plates, and add 150 ⁇ L of reagent.
- the maximum concentration of the reagent was 200 ⁇ g/mL, which was decreased by 50% variable gradient, which was 200.00 ⁇ g/mL, 100.00 ⁇ g/mL 50.00 ⁇ g/mL 25.00 ⁇ g/mL 12.50 ⁇ g/mL 6.25 ⁇ g/ 8 concentrations of mL, 3.13 ⁇ g/mL and 1.06 ⁇ g/mL.
- DMS0 dimethyl sulfoxide 150 ⁇ was added to each well, and placed in a carbon dioxide incubator for 10 min, and a 96-well microplate reader was used to measure the absorbance at a wavelength of 490 nm.
- Figure 1 Comparison of growth inhibition rates of 24 coumarin derivatives and CA4 versus EVC-304 cells.
- Compound 2 was prepared by the procedure of Example 1, substituting toluene for benzene. Mass Spectrum: ⁇ / ⁇ [ ⁇ +1] + , 293.
- Example 3 Preparation of 7-methoxy-8-[2-(3,4-dimethylphenyl)]vinylcoumarin (Compound 4) According to the method of Example 1, a compound was prepared by replacing o-xylene with benzene. 4. Mass Spectrum: ⁇ / ⁇ [ ⁇ +1] + , 307.
- Example 4 Preparation of 7-Methoxy-8-[2-[(benzo[1,2, a]cyclopentanyl)-4-yl]vinylcoumarin (Compound 5)
- Example 8 Preparation of 7-methoxy-8-[2-(3,4-dimethoxyphenyl)]vinylcoumarin (Compound 9) Following the procedure of Example 1, substituting o-dimethoxybenzene Compound 9 was prepared from benzene. Mass Spectrum: ⁇ / ⁇ [ ⁇ +1] + , 339.
- Example 9 Preparation of 7-methoxy-8-[2-(3,4-dihydroxyphenyl)]vinylcoumarin (Compound 10) According to the method of Example 1, a compound was prepared by replacing benzene with catechol. 10. Mass Spectrum: ⁇ / ⁇ [ ⁇ +1] + , 311.
- Example 10 Preparation of 7-methoxy-8-[2-(2,3,4-trimethoxyphenyl)]vinylcoumarin (Compound 11)
- Example 11 Preparation of 7-methoxy-8-[2-(2,3,4-trihydroxyphenyl)]vinylcoumarin (Compound 12) According to the method of Example 1, 1, 2, 3 - Compound 12 was prepared by replacing benzene with benzenetriol. Mass spectrometry: ⁇ / ⁇ [ ⁇ +1] + ,
- the compound 7-methoxy-8-[2-(4-acetamidophenyl)]vinylcoumarin was prepared by replacing benzene with acetanilide.
- Example 20 Preparation of 7-Methoxy-8-[2-(2-methoxy-5-(indolyl)aminophenyl)]vinylcoumarin (Compound 21)
- 4-methoxy-(N-ethyl)acetanilide was used instead of benzene to prepare compound 7-methoxy-8-[2-(2-methoxy-5-(N-ethyl) ) Acetylaminophenyl)]vinylcoumarin.
- 7-methoxy-8-[2-(2-methoxy-5-(N-ethyl)aminophenyl)]vinylcoumarin (Compound 21) was hydrolyzed according to the method of Example 14. Mass Spectrum: M/Z [M+1] + , 322.
- Example 21 Preparation of 7-Methoxy-8-[2-(2-hydroxy-5-aminophenyl)]vinylcoumarin (Compound 22)
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Abstract
Coumarin derivatives represented by general formula (I), their preparation methods, and their uses as angiogenesis inhibitors for the treatment of tumor and angio-retina diseases. This type of compounds is obtained by modification based on the structure of osthol. Vascular endothelial cell growth inhibiting experiments show that compounds of formula (I) have obvious EVC-304 cell multiplication inhibiting activity. Compared with combretastatin A-4 (CA4), the inhibiting activity of formula (I) is stronger and 1.5-4.0 times the activity of CA4.
Description
说明书 一种香豆素衍生物及其制备方法和用途 技术领域 Coumarin derivative, preparation method and use thereof
本发明涉及一种香豆素衍生物及其制备方法以及作为血管生成抑制剂在治疗肿瘤及 血管性视网膜病变中的应用。 The present invention relates to a coumarin derivative, a process for its preparation and the use as an angiogenesis inhibitor for the treatment of tumors and vascular retinopathy.
肿瘤的生长、 转移、 复发、 预后与血管生成密切相关， 以肿瘤的血管生成为靶点， 可 能使实体瘤的治疗效果得到较大提高。血管生成抑制作用对象是不同肿瘤组织中几乎相同 的血管内皮细胞，这种肿瘤血管内皮细胞除分裂增殖速度较快之外与正常内皮细胞相比并 无明显差别。 正常内皮细胞寿命较长， 基因型稳定。 除了神经细胞以外， 内皮细胞是体内 寿命最长的细胞之一。 存在于成年血管壁上的内皮细胞， 同一时间内只有 0. 01 %左右处 于分裂状态， 肿瘤血管内皮细胞增殖速度较正常组织中的内皮细胞增殖速度大约高 50倍 以上。因此使用血管抑制因子对肿瘤血管有相对特异性作用，而对正常组织内的血管不会 造成明显影响。 endostatin和 angiostatin虽是目前已知的较强的内源性血管生成抑制 剂，但生产这类高纯度安全制剂工艺需较高的技术门槛， 以及这些活性蛋白在体内较短的 半衰期等因素的影响，从而限制了这些活性蛋白的临床应用。因此在小分子化合物中寻求 血管生成抑制剂已成为研究重点。 combretastatin A-4 ( CA4) 为南非 Combretum caffrum树干中提取分离的具有抗肿 瘤活性的二苯乙烯类化合物 （美国专利 4996237， Feb , 22 , 1988 ) 。 由于该化合物溶解 性差，经磷酸化生产前药 combretastatin A-4 磷酸钠 （CA4P) (美国专利 5561122， Dec , 22 , 1994) ， 其体内抗肿瘤活性大大提高， CA4P在体内迅速去磷酸化生成 CA4， 血浆半衰 期为 30min。 CA4直接作用于内皮细胞， 诱导增殖的内皮细胞凋亡， 从而抑制血管生成。 Tumor growth, metastasis, recurrence, and prognosis are closely related to angiogenesis. Targeting tumor angiogenesis can greatly improve the therapeutic effect of solid tumors. The angiogenesis inhibitory effect is almost the same vascular endothelial cells in different tumor tissues. This tumor vascular endothelial cells have no significant difference compared with normal endothelial cells except for the rapid proliferation rate. Normal endothelial cells have a long life span and a stable genotype. In addition to nerve cells, endothelial cells are one of the longest-lived cells in the body. The endothelial cells present on the wall of adult blood vessels were only about 0.01% in the split state at the same time. The proliferation rate of tumor vascular endothelial cells was about 50 times higher than that of normal tissues. Therefore, the use of angiogenesis inhibitors has a relatively specific effect on tumor blood vessels, but does not significantly affect blood vessels in normal tissues. Although endostatin and angiostatin are currently known as strong endogenous angiogenesis inhibitors, the production of such high-purity safe preparations requires high technical thresholds and the effects of these active proteins on short half-lives in vivo. This limits the clinical application of these active proteins. Therefore, the search for angiogenesis inhibitors in small molecule compounds has become the focus of research. Combretastatin A-4 (CA4) is a stilbene compound with antitumor activity isolated from the trunk of Combretum caffrum in South Africa (US Patent 4996237, Feb, 22, 1988). Due to the poor solubility of this compound, phosphorylation of the prodrug combertastatin A-4 sodium phosphate (CA4P) (US Patent 5,561,122, Dec, 22, 1994), its anti-tumor activity is greatly improved, CA4P rapidly dephosphorylates in vivo to form CA4 The plasma half-life is 30 min. CA4 acts directly on endothelial cells to induce proliferation of proliferating endothelial cells, thereby inhibiting angiogenesis.
CA4P 不仅在实体瘤上的研究取得进展， 在治疗各种眼科疾病状况下异常血管形成方 面亦取得突破性进展，特别是在治疗糖尿病晚期患者因血管性视网膜病变引起视觉模糊和 失明， 有可能成为治疗血管增生性视网膜病变的新型药物。
combretastatin A-4 蛇床子素 （osthol ) 是从中药蛇床子中提取一种香豆素类化合物。 近年来有研究表 明，蛇床子素能不同程度地抑制肺腺癌和肺鳞癌的生长，蛇床子水提液能较明显地抑制昆 明种小鼠 S180肉瘤的生长。 血管内皮细胞抑制作用研究表明，蛇床子素具有明显的 EVC— 304抑制作用，但与 CA4 相比作用较弱。在蛇床子素的结构基础上进行结构修饰， 保持香豆素基本结构， 引入二苯 乙烯官能团得到一系列衍生物。 香豆素衍生物 EVC— 304抑制作用是 CA4的 1. 5〜10倍。 发明内容 CA4P has not only made progress in the study of solid tumors, but also made breakthroughs in the treatment of abnormal angiogenesis in various ophthalmic diseases. Especially in the treatment of patients with advanced diabetes, visual blur and blindness caused by vascular retinopathy may become A new drug for the treatment of vascular proliferative retinopathy. Combrastastatin A-4 Osthol is a coumarin compound extracted from the Chinese medicine Cnidium. In recent years, studies have shown that osthole can inhibit the growth of lung adenocarcinoma and lung squamous cell carcinoma to varying degrees. The aqueous extract of Cnidium can significantly inhibit the growth of S180 sarcoma in Kunming mice. Vascular endothelial cell inhibition studies have shown that osthole has a significant inhibitory effect on EVC-304, but it is weaker than CA4. Structural modification on the structure of osthole, maintaining the basic structure of coumarin, and introducing a stilbene functional group to obtain a series of derivatives. 5〜10倍。 The coumarin derivative EVC-304 inhibition is CA. Summary of the invention
本发明的目的在于提供一种具有药用价值的香豆素衍生物。 It is an object of the present invention to provide a coumarin derivative having medicinal value.
本发明的另一目的在于提供一种香豆素衍生物的制备方法。 Another object of the present invention is to provide a process for preparing a coumarin derivative.
本发明进一步的目的在于提供上述化合物或其药学上可接受的盐作为血管生成 抑制剂在制备治疗抗肿瘤药物中的应用。 本发明进一步的目的还在于提供上述化合物或其药学上可接受的盐作为血管生 成抑制剂在制备治疗血管性视网膜病变药物中的应用。 本发明的目的可以通过以下措施来达到： A further object of the present invention is to provide the use of the above compound or a pharmaceutically acceptable salt thereof as an angiogenesis inhibitor for the preparation of a therapeutic antitumor drug. A further object of the present invention is to provide the use of the above compound or a pharmaceutically acceptable salt thereof as an angiogenesis inhibitor for the preparation of a medicament for treating vascular retinopathy. The object of the present invention can be achieved by the following measures:
本发明香豆素衍生物用下述通式 （I ) 表示， 该类化合物是在蛇床子素的结构基础上 进行修饰得到。
The coumarin derivative of the present invention is represented by the following formula (I), which is obtained by modifying the structure of osthole.
本发明还可以通过下述方法制得:
The invention can also be obtained by the following method:
其中， Rl、 R2、 R3、 R4或 R5分别代表氢、 氨基或者取代氨基、 垸基或取代垸 基或 OM， 其中 M为氢、 垸基或者取代垸基或磷酸基及其盐。 给出了本发明实施例的香豆素衍生物。 Wherein R1, R2, R3, R4 or R5 represents hydrogen, amino or substituted amino, fluorenyl or substituted fluorenyl or OM, respectively, wherein M is hydrogen, fluorenyl or substituted fluorenyl or phosphoric acid and salts thereof. The coumarin derivatives of the examples of the invention are given.
表 1 Table 1
细胞培养 EVC— 304细胞以 1 107个/11^密度接种于含 10%小牛血清、 100U/mL 青、 链霉素 RPMI— 1640培养液中 （pH7.4)， 5%二氧化碳恒温培养箱 37 °C培养， 每隔 48h
换液 1次， 待细胞长满后用 0.25%胰蛋白酶消化， 收集并传代。 试验选用换液 24h后对数 生长期细胞。 Cell culture Cells EVC- 304 10 7 1/11 ^ seeded containing 10% calf serum, 100U / mL penicillin and streptomycin RPMI- 1640 culture medium (pH7.4), 5% carbon dioxide incubator Culture at 37 °C, every 48h The solution was changed once, and after the cells were over, they were digested with 0.25% trypsin, collected and passaged. In the experiment, the logarithmic growth phase cells were selected after 24 hours of fluid exchange.
MTT (二甲基噻唑二苯基四唑溴盐）试验 对数生长期 EVC— 304细胞， 用 0.25%胰 蛋白酶消化 3〜5min， 用培养基终止消化， 调整细胞浓度 5 X 104个 /mL， 按 150 μί/孔接 种于 96孔板， 再加入 150 μ L试药。 试药最大浓度为 200 μ g/mL, 以 50%变量梯度递减， 分别为 200.00μ g/mL、 100.00μ g/mL 50.00μ g/mL 25.00μ g/mL 12.50μ g/mL 6.25 μ g/mL, 3.13 μ g/mL和 1.06 μ g/mL8个浓度。每试药浓度设 10孔。培养 24h加入 5mg/mL 无菌 MTT每孔 20 μί。 继续培养 4h后去培养基， 每孔各加 DMS0 (二甲亚砜） 150 μί， 放 入二氧化碳培养箱 10min， 96孔酶标仪， 490nm波长测定吸收度。 MTT (dimethylthiazole diphenyltetrazolium bromide) test EVC-304 cells in logarithmic growth phase, digested with 0.25% trypsin for 3~5min, terminate digestion with medium, adjust cell concentration 5 X 10 4 /mL , inoculate 150 μί/well in 96-well plates, and add 150 μL of reagent. The maximum concentration of the reagent was 200 μg/mL, which was decreased by 50% variable gradient, which was 200.00 μg/mL, 100.00 μg/mL 50.00 μg/mL 25.00 μg/mL 12.50 μg/mL 6.25 μg/ 8 concentrations of mL, 3.13 μg/mL and 1.06 μg/mL. Set 10 wells per reagent. Add 24 μg per well to 5 mg/mL sterile MTT for 24 h. After continuing to culture for 4 hours, the medium was removed, and DMS0 (dimethyl sulfoxide) 150 μί was added to each well, and placed in a carbon dioxide incubator for 10 min, and a 96-well microplate reader was used to measure the absorbance at a wavelength of 490 nm.
细胞生长抑制率
Cell growth inhibition rate
对照孔 A值一空白孔 A值） Control hole A value - blank hole A value)
表 2:香豆素衍生物和 CA4对 EVC— 304细胞生长抑制 MTT试验结果 Table 2: Coumarin derivatives and CA4 on EVC-304 cell growth inhibition MTT test results
21 0 5. 5 23. 1 41. 4 61. 1 88. 2 100. 0 100. 0 14. 9821 0 5. 5 23. 1 41. 4 61. 1 88. 2 100. 0 100. 0 14. 98
22 0 7. 3 29. 2 41. 3 65. 8 93. 1 100. 0 100. 0 14. 0822 0 7. 3 29. 2 41. 3 65. 8 93. 1 100. 0 100. 0 14. 08
23 0 5. 9 22. 3 36. 7 59. 1 82. 1 100. 0 100. 0 15. 4723 0 5. 9 22. 3 36. 7 59. 1 82. 1 100. 0 100. 0 15. 47
24 0 2. 1 15. 9 32. 7 55. 3 69. 2 85. 2 100. 0 22. 52 本发明的有益效果 24 0 2. 1 15. 9 32. 7 55. 3 69. 2 85. 2 100. 0 22. 52 Benefits of the invention
在蛇床子素的结构基础上进行结构修饰，保持香豆素基本结构， 引入二苯乙烯官能团 得到一系列衍生物， 血管内皮细胞抑制作用试验表明， 该衍生物具有明显的 EVC— 304细 胞增殖抑制作用。 与 combretastatin A-4 ( CA4) 相比， 香豆素衍生物 EVC— 304抑制作 用是 CA4的 1. 5〜10倍。 附图说明 Structural modification on the structure of osthole, maintaining the basic structure of coumarin, introducing a stilbene functional group to obtain a series of derivatives, vascular endothelial cell inhibition test showed that the derivative has obvious inhibition of cell proliferation of EVC-304 cells. effect. Compared with combretastatin A-4 (CA4), the coumarin derivative EVC-304 inhibited the action to be 1. 5 to 10 times that of CA4. DRAWINGS
图 1. 24个香豆素衍生物和 CA4对 EVC— 304细胞生长抑制率比较图 具体实施方式 Figure 1. Comparison of growth inhibition rates of 24 coumarin derivatives and CA4 versus EVC-304 cells.
实施例 1 制备 7—甲氧基一 8— （2—苯基） 乙烯基香豆素 （化合物 1 ) Example 1 Preparation of 7-methoxy-8-(2-phenyl)vinylcoumarin (Compound 1)
7-甲氧基香豆素一 8—乙酸的制备 Preparation of 7-methoxycoumarin-8-acetic acid
15°C以下， 加入冰醋酸 350ml， 蛇床子素 30g， 搅拌下分数批加入三氧化铬 40g， 加 毕， 20〜25°C继续搅拌反应 4h， 反应完毕， 加入冰水 lOOOml , 过滤， 水洗涤得 7-甲氧基 香豆素一 8—乙酸 12. 6g。 Below 15 °C, add 350 ml of glacial acetic acid, 30 g of osthole, and add 40 g of chromium trioxide in portions with stirring. Add the mixture and continue stirring for 4 h at 20~25 °C. After the reaction is completed, add 1000 ml of ice water, filter, and wash with water. 7克。 7-methoxycoumarin-8-acetic acid 12. 6g.
7—甲氧基一 8— （2—氧代一 2—苯基） 乙基香豆素的制备 Preparation of 7-methoxy-8-(2-oxo-2-phenyl)ethylcoumarin
二氯甲垸 300ml， 7—甲氧基香豆素一 8—乙酸 20g， 搅拌下加入氯化亚砜 20ml， 室温
搅拌反应过夜， 减压回收溶剂至干， 加入二硫化碳 100ml溶解备用。 Dichloromethane 300ml, 7-methoxycoumarin-8-acetic acid 20g, add 20ml of thionyl chloride under stirring, room temperature The reaction was stirred overnight, and the solvent was evaporated to dryness under reduced pressure.
二硫化碳 500ml， 苯 100ml， 冰盐浴冷却一 5°C以下， 搅拌下加入无水三氯化铝 50g， 保持温度一 5°C以下， 搅拌下滴加上述备用液， 加毕， 室温反应过夜， 将反应液下加入到 1000ml冰水混合物中， 分出有机层， 回收溶剂得到 7—甲氧基一 8—（2—氧代一 2—苯基) 乙基香豆素 28. 9g。 500ml of carbon disulfide, 100ml of benzene, cooled to 5°C in ice salt bath, add 50g of anhydrous aluminum trichloride under stirring, keep the temperature below 5 °C, add the above reserve solution with stirring, add, and react at room temperature overnight. 5克。 The reaction mixture was added to a mixture of water and a mixture of the mixture was added to the mixture.
7—甲氧基一 8— （2—羟基一 2—苯基） 乙基香豆素的制备 Preparation of 7-methoxy-8-(2-hydroxy-2-phenyl)ethylcoumarin
无水乙醇 450ml， 7—甲氧基一 8— （2—氧代一 2—苯基） 乙基香豆素 30g， 冰浴冷却 下， 分数批加入硼氢化钠 1. 8g， 加毕， 继续 0°C左右反应 4h， 反应完毕， 搅拌下将反应 液加入到 5 %氯化铵水溶液 1000ml中， 用二氯甲垸提取， 得到 7—甲氧基一 8—（2—羟基 一 2—苯基） 乙基香豆素 30g。 Anhydrous ethanol, 450 ml, 7-methoxy-8-(2-oxo-2-phenyl) ethyl coumarin 30 g, ice-cooled, fractionally added sodium borohydride 1. 8 g, add, continue After reacting at 0 ° C for 4 h, the reaction was completed, and the reaction solution was added to 1000 ml of a 5 % ammonium chloride aqueous solution with stirring, and extracted with dichloromethane to obtain 7-methoxy-8-(2-hydroxy-2-phenylene). Base) Ethyl coumarin 30g.
7—甲氧基一 8— （2—苯基） 乙烯基香豆素 （化合物 1 ) 的制备 Preparation of 7-methoxy-8-(2-phenyl)vinylcoumarin (Compound 1)
7—甲氧基一 8— （2—羟基一 2—苯基） 乙基香豆素 2g， 冰醋酸 150ml， 无水乙酸钠 5g, 90〜100°C搅拌反应 2h， 反应完毕， 减压回收溶剂至干， 用冰水洗涤得到 7—甲氧基 -8- ( 2—苯基） 乙烯基香豆素 （化合物 1 ) 1. 6g。 质谱： Μ/Ζ [Μ+1] +， 279。 实施例 2 制备 7—甲氧基一 8— [2—（4一甲基苯基) ]乙烯基香豆素 （化合物 2 ) 7-methoxy-8-(2-hydroxy-2-phenyl)ethylcoumarin 2g, glacial acetic acid 150ml, anhydrous sodium acetate 5g, stirred at 90~100 °C for 2h, the reaction is completed, vacuum recovery The solvent was dried to dryness and washed with ice water to give <RTIgt;</RTI>> 7-methoxy-8-(2-phenyl)vinylcoumarin (Compound 1) 1. 6 g. Mass Spectrum: Μ/Ζ [Μ+1] + , 279. Example 2 Preparation of 7-methoxy-8-[2-(4-methylphenyl)]vinylcoumarin (Compound 2)
按照实施例 1方法， 以甲苯代替苯制备化合物 2。 质谱： Μ/Ζ [Μ+1] +， 293。 实施例 3 制备 7—甲氧基一 8— [2—（3， 4一二甲基苯基) ]乙烯基香豆素 （化合物 4) 按照实施例 1方法， 以邻二甲苯代替苯制备化合物 4。 质谱： Μ/Ζ [Μ+1] +， 307。
实施例 4 制备 7—甲氧基一 8— [2- [ (苯并 [1， 2， a]环戊垸）一 4一基]乙烯基香豆素（化 合物 5) Compound 2 was prepared by the procedure of Example 1, substituting toluene for benzene. Mass Spectrum: Μ/Ζ [Μ+1] + , 293. Example 3 Preparation of 7-methoxy-8-[2-(3,4-dimethylphenyl)]vinylcoumarin (Compound 4) According to the method of Example 1, a compound was prepared by replacing o-xylene with benzene. 4. Mass Spectrum: Μ/Ζ [Μ+1] + , 307. Example 4 Preparation of 7-Methoxy-8-[2-[(benzo[1,2, a]cyclopentanyl)-4-yl]vinylcoumarin (Compound 5)
按照实施例 1方法， 以苯并 [1， 2， a]环戊垸代替苯制备化合物 5。 质谱： Μ/Ζ[Μ+1] +，Compound 5 was prepared by the procedure of Example 1, substituting benzo[1,2, a]cyclopentanyl for benzene. Mass spectrometry: Μ/Ζ[Μ+1] + ,
319。 319.
实施例 5 制备 7-甲氧基一8— [2- [ (苯并 [1， 2， a]环己垸）一4一基]乙烯基香豆素（化 合物 6) Example 5 Preparation of 7-Methoxy-8-[2-[(benzo[1,2, a]cyclohexanyl)-4-yl]vinylcoumarin (Compound 6)
按照实施例 1方法， 以苯并 [1， 2， a]环己垸代替苯制备化合物 6。 质谱： Μ/Ζ[Μ+1] +，Compound 6 was prepared according to the procedure of Example 1 by substituting benzo[1,2, a]cyclohexane for benzene. Mass spectrometry: Μ/Ζ[Μ+1] + ,
333。 实施例 6 制备 7—甲氧基一 8— [2—（4一甲氧基苯基)]乙烯基香豆素 （化合物 7) 333. Example 6 Preparation of 7-methoxy-8-[2-(4-methoxyphenyl)]vinylcoumarin (Compound 7)
按照实施例 1方法， 以苯甲醚代替苯制备化合物 7。 质谱： Μ/Ζ[Μ+1] +， 309。 实施例 7 制备 7—甲氧基一 8— [2—（4一羟基苯基)]乙烯基香豆素 （化合物 8) Compound 7 was prepared according to the procedure of Example 1 by replacing the benzene with anisole. Mass Spectrum: Μ/Ζ[Μ+1] + , 309. Example 7 Preparation of 7-Methoxy-8-[2-(4-hydroxyphenyl)]vinylcoumarin (Compound 8)
按照实施例 1方法， 以苯酚代替苯制备化合物 8。 质谱： Μ/Ζ[Μ+1] +， 295。 实施例 8 制备 7—甲氧基一 8— [2—（3， 4一二甲氧基苯基)]乙烯基香豆素 （化合物 9) 按照实施例 1方法， 以邻二甲氧苯代替苯制备化合物 9。 质谱： Μ/Ζ[Μ+1] +， 339。 实施例 9 制备 7—甲氧基一 8— [2—（3， 4一二羟基苯基)]乙烯基香豆素 （化合物 10) 按照实施例 1方法， 以邻苯二酚代替苯制备化合物 10。 质谱： Μ/Ζ[Μ+1] +， 311。 实施例 10 制备 7—甲氧基一 8— [2—（2， 3， 4一三甲氧基苯基)]乙烯基香豆素 （化合物 11) Compound 8 was prepared according to the procedure of Example 1 by substituting phenol for benzene. Mass Spectrum: Μ/Ζ[Μ+1] + , 295. Example 8 Preparation of 7-methoxy-8-[2-(3,4-dimethoxyphenyl)]vinylcoumarin (Compound 9) Following the procedure of Example 1, substituting o-dimethoxybenzene Compound 9 was prepared from benzene. Mass Spectrum: Μ/Ζ[Μ+1] + , 339. Example 9 Preparation of 7-methoxy-8-[2-(3,4-dihydroxyphenyl)]vinylcoumarin (Compound 10) According to the method of Example 1, a compound was prepared by replacing benzene with catechol. 10. Mass Spectrum: Μ/Ζ[Μ+1] + , 311. Example 10 Preparation of 7-methoxy-8-[2-(2,3,4-trimethoxyphenyl)]vinylcoumarin (Compound 11)
按照实施例 1方法， 以 1， 2, 3—三甲氧基苯代替苯制备化合物 11。质谱： Μ/Ζ[Μ+1] + ,Compound 11 was prepared by the procedure of Example 1, substituting 1,2,3-trimethoxybenzene for benzene. Mass spectrometry: Μ/Ζ[Μ+1] + ,
369。
实施例 11 制备 7—甲氧基一 8— [2- (2， 3， 4一三羟基苯基) ]乙烯基香豆素 (化合物 12) 按照实施例 1方法， 以 1， 2, 3—苯三酚代替苯制备化合物 12。 质谱： Μ/Ζ[Μ+1] +，369. Example 11 Preparation of 7-methoxy-8-[2-(2,3,4-trihydroxyphenyl)]vinylcoumarin (Compound 12) According to the method of Example 1, 1, 2, 3 - Compound 12 was prepared by replacing benzene with benzenetriol. Mass spectrometry: Μ/Ζ[Μ+1] + ,
328。 实施例 12 制备 7—甲氧基一8—[2— [(苯并 [l，2，d] (1， 3—二氧杂）环戊焼）一4一基] 乙烯基香豆素 （化合物 13) 328. Example 12 Preparation of 7-methoxy-8-[2-[(benzo[l,2,d](1,3-dioxa)cyclopentanyl)-4-yl]vinylcoumarin ( Compound 13)
按照实施例 1方法， 以苯并 [l，2，d] (1， 3—二氧杂） 环戊垸代替苯制备化合物 13。 质谱： Μ/Ζ[Μ+1]+， 323。 实施例 13 制备 7—甲氧基一8—[2— [(苯并 [l，2，b] (1， 4一二氧杂）环己焼）一4一基] 乙烯基香豆素 （化合物 14) Compound 13 was prepared by the procedure of Example 1, using benzo[l,2,d](1,3-dioxa)cyclopentanyl in place of benzene. Mass Spectrum: Μ/Ζ[Μ+1] + , 323. Example 13 Preparation of 7-Methoxy-8-[2-[(benzo[l,2,b](1,4-dioxa)cyclohexanyl)-4-yl]vinylcoumarin ( Compound 14)
按照实施例 1方法， 以苯并 [l，2，b] (1， 4一二氧杂） 环己垸代替苯制备化合物 14。 质谱： Μ/Ζ[Μ+1]+， 351。 实施例 14 制备 7—甲氧基一 8— [2—（4一氨基苯基)]乙烯基香豆素 （化合物 15) Compound 14 was prepared by the procedure of Example 1, substituting benzo[l,2,b](1,4-dioxa)cyclohexane for benzene. Mass Spectrum: Μ/Ζ[Μ+1] + , 351. Example 14 Preparation of 7-Methoxy-8-[2-(4-aminophenyl)]vinylcoumarin (Compound 15)
按照实施例 1方法， 以乙酰苯胺代替苯制备化合物 7—甲氧基一 8— [2—（4一乙酰氨 基苯基)]乙烯基香豆素。 According to the method of Example 1, the compound 7-methoxy-8-[2-(4-acetamidophenyl)]vinylcoumarin was prepared by replacing benzene with acetanilide.
7—甲氧基一 8— [2—（4一氨基苯基)]乙烯基香豆素 （化合物 15) 的制备 Preparation of 7-methoxy-8-[2-(4-aminophenyl)]vinylcoumarin (Compound 15)
7—甲氧基一 8— [2- (4一乙酰氨基苯基） ]乙烯基香豆素 5g，乙醇 100ml，浓盐酸 50ml， 55°C搅拌反应 4h， 反应完毕， 减压回收溶剂至干， 用冰水洗涤得到 7—甲氧基一 8— [2— (4一氨基苯基）]乙烯基香豆素 （化合物 15) 4. lg。 质谱： Μ/Ζ[Μ+1] +， 294。 实施例 15 制备 7—甲氧基一 8— [2—（4一 （Ν—甲基）氨基苯基)]乙烯基香豆素（化合 物 16) 7-methoxy-8-[2-(4-acetamidophenyl)]vinylcoumarin 5g, ethanol 100ml, concentrated hydrochloric acid 50ml, stirred at 55 ° C for 4h, the reaction is completed, the solvent is recovered under reduced pressure to dry Washed with ice water to give 7-methoxy-8-[2-(4-aminophenyl)]vinylcoumarin (Compound 15) 4. lg. Mass spectrometry: Μ/Ζ[Μ+1] + , 294. Example 15 Preparation of 7-Methoxy-8-[2-(4-(indolyl)aminophenyl)]vinylcoumarin (Compound 16)
按照实施例 1方法， 以 Ν -甲基乙酰苯胺代替苯制备化合物 7—甲氧基一 8— [2- (4 - (Ν—甲基） 乙酰氨基苯基)]乙烯基香豆素。 再按照实施例 14 方法水解制备 7—甲氧 基一 8— [2—（4一 （Ν—甲基） 氨基苯基）]乙烯基香豆素 （化合物 16)。 质谱： Μ/Ζ[Μ+1] +， 308。
实施例 16 制备 7—甲氧基一 8— [2—（4一 （N—乙基）氨基苯基) ]乙烯基香豆素（化合 物 17 ) The compound 7-methoxy-8-[2-(4-(indolyl)acetamidophenyl)]vinylcoumarin was prepared by the procedure of Example 1, using hydrazine-methylacetanilide instead of benzene. Further, 7-methoxy-8-[2-(4-(indolyl)methylphenyl)]vinylcoumarin (Compound 16) was hydrolyzed according to the method of Example 14. Mass Spectrum: Μ/Ζ[Μ+1] + , 308. Example 16 Preparation of 7-methoxy-8-[2-(4-(ethyl)aminophenyl)]vinylcoumarin (Compound 17)
按照实施例 1方法， 以 N -乙基乙酰苯胺代替苯制备化合物 7—甲氧基一 8— [2—（4 - (N—乙基） 乙酰氨基苯基) ]乙烯基香豆素。 再按照实施例 14 方法水解制备 7—甲氧 基一 8— [2—（4一 （N—乙基） 氨基苯基）]乙烯基香豆素 （化合物 17)。 质谱： Μ/Ζ [Μ+1] +， The compound 7-methoxy-8-[2-(4-(4-ethyl)acetamidophenyl)]vinylcoumarin was prepared according to the procedure of Example 1 by substituting N-ethylacetanilide for benzene. Further, 7-methoxy-8-[2-(4-(ethyl)ethylphenyl)]vinylcoumarin (Compound 17) was hydrolyzed according to the method of Example 14. Mass Spectrum: Μ/Ζ [Μ+1] + ,
实施例 17 制备 7—甲氧基一8—[2—（4一 （Ν， Ν， 二甲基氨基） 苯基) ]乙烯基香豆素 (化合物 18 ) Example 17 Preparation of 7-Methoxy-8-[2-(4-(indolyl, dimethylamino)phenyl)]vinylcoumarin (Compound 18)
按照实施例 1方法， 以^ Ν—二甲基苯胺代替苯制备化合物 18。 质谱： Μ/Ζ [Μ+1] +， Compound 18 was prepared according to the procedure of Example 1 by substituting benzene-dimethylaniline for benzene. Mass Spectrum: Μ/Ζ [Μ+1] + ,
实施例 18 制备 7—甲氧基一 8— [2— （2-甲氧基一 5—氨基苯基) ]乙烯基香豆素（化合 物 19 ) Example 18 Preparation of 7-methoxy-8-[2-(2-methoxy-5-aminophenyl)]vinylcoumarin (Compound 19)
按照实施例 1方法，以 4一甲氧基乙酰苯胺代替苯制备化合物 7—甲氧基一 8— [2- ( 2- 甲氧基一 5—乙酰氨基苯基） ]乙烯基香豆素。 再按照实施例 14 方法水解制备 7—甲氧基 一 8— [2— （2-甲氧基一 5—氨基苯基） ]乙烯基香豆素 （化合物 19)。 质谱： Μ/Ζ [Μ+1] +， 324。 实施例 19 制备 7—甲氧基一 8— [2— （2-甲氧基一 5— （Ν—甲基）氨基苯基） ]乙烯基 香豆素 （化合物 20 ) The compound 7-methoxy-8-[2-(2-methoxy-5-acetamidophenyl)]vinylcoumarin was prepared according to the procedure of Example 1 by substituting 4-methoxyacetanilide for benzene. Further, 7-methoxy-8-[2-(2-methoxy-5-aminophenyl)]vinylcoumarin (Compound 19) was hydrolyzed according to the method of Example 14. Mass Spectrum: Μ/Ζ [Μ+1] + , 324. Example 19 Preparation of 7-methoxy-8-[2-(2-methoxy-5-(indolyl)aminophenyl)]vinylcoumarin (Compound 20)
按照实施例 1方法， 以 4一甲氧基一（Ν—甲基）乙酰苯胺代替苯制备化合物 7—甲氧 基一 8— [2— （2-甲氧基一 5— （Ν—甲基） 乙酰氨基苯基） ]乙烯基香豆素。 再按照实施例 14 方法水解制备 7—甲氧基一 8— [2— （2-甲氧基一 5— （Ν—甲基） 氨基苯基） ]乙烯基 香豆素 (化合物 20)。 质谱： Μ/Ζ [Μ+1] + , 338。 实施例 20 制备 7—甲氧基一 8— [2— （2-甲氧基一 5— （Ν—乙基）氨基苯基） ]乙烯基 香豆素 （化合物 21 )
按照实施例 1方法， 以 4一甲氧基一（N—乙基）乙酰苯胺代替苯制备化合物 7—甲氧 基一 8— [2— （2-甲氧基一 5— （N—乙基） 乙酰氨基苯基） ]乙烯基香豆素。 再按照实施例 14 方法水解制备 7—甲氧基一 8— [2— （2-甲氧基一 5— （N—乙基） 氨基苯基） ]乙烯基 香豆素 （化合物 21 )。 质谱： M/Z [M+1] + , 322。 实施例 21 制备 7—甲氧基一 8— [2— （2-羟基一 5—氨基苯基） ]乙烯基香豆素 （化合 物 22 ) According to the method of Example 1, 4-methoxy-(indolyl)acetanilide was used instead of benzene to prepare compound 7-methoxy-8-[2-(2-methoxy-5-(indole-methyl) ) Acetylaminophenyl)]vinylcoumarin. Further, 7-methoxy-8-[2-(2-methoxy-5-(indolyl)aminophenyl)]vinylcoumarin (Compound 20) was hydrolyzed according to the method of Example 14. Mass Spectrum: Μ/Ζ [Μ+1] + , 338. Example 20 Preparation of 7-Methoxy-8-[2-(2-methoxy-5-(indolyl)aminophenyl)]vinylcoumarin (Compound 21) According to the method of Example 1, 4-methoxy-(N-ethyl)acetanilide was used instead of benzene to prepare compound 7-methoxy-8-[2-(2-methoxy-5-(N-ethyl) ) Acetylaminophenyl)]vinylcoumarin. Further, 7-methoxy-8-[2-(2-methoxy-5-(N-ethyl)aminophenyl)]vinylcoumarin (Compound 21) was hydrolyzed according to the method of Example 14. Mass Spectrum: M/Z [M+1] + , 322. Example 21 Preparation of 7-Methoxy-8-[2-(2-hydroxy-5-aminophenyl)]vinylcoumarin (Compound 22)
按照实施例 1方法， 以 4一羟基乙酰苯胺代替苯制备化合物 7—甲氧基一 8— [2— ( 2- 羟基一 5—乙酰氨基苯基） ]乙烯基香豆素。再按照实施例 14 方法水解制备 7—甲氧基一 8— [2— （2-羟基一 5—氨基苯基） ]乙烯基香豆素 （化合物 22)。 质谱： Μ/Ζ [Μ+1] +， 310。 实施例 22 制备 7—甲氧基一 8— [2— （2-羟基一 5— （Ν—甲基）氨基苯基） ]乙烯基香 豆素 （化合物 23 ) The compound 7-methoxy-8-[2-(2-hydroxy-5-acetamidophenyl)]vinylcoumarin was prepared according to the procedure of Example 1 by substituting 4-hydroxyacetanilide for benzene. Further, 7-methoxy-8-[2-(2-hydroxy-5-aminophenyl)]vinylcoumarin (Compound 22) was hydrolyzed according to the method of Example 14. Mass Spectrum: Μ/Ζ [Μ+1] + , 310. Example 22 Preparation of 7-methoxy-8-[2-(2-hydroxy-5-(indolyl)aminophenyl)]vinylcoumarin (Compound 23)
按照实施例 1方法， 以 4一羟基一（Ν—甲基）乙酰苯胺代替苯制备化合物 7—甲氧基 一 8— [2—（2-羟基一 5—（Ν—甲基）乙酰氨基苯基）]乙烯基香豆素。再按照实施例 14 方 法水解制备 7—甲氧基一 8— [2- ( 2-羟基一 5—（Ν—甲基）氨基苯基） ]乙烯基香豆素（化 合物 23)。 质谱： Μ/Ζ [Μ+1] +， 324。 实施例 23 制备 7—甲氧基一 8— [2— （2-羟基一 5— （Ν—乙基）氨基苯基） ]乙烯基香 豆素 （化合物 24) According to the method of Example 1, 4-hydroxy-(indolyl)acetanilide was used instead of benzene to prepare compound 7-methoxy-8-[2-(2-hydroxy-5-(indolyl)acetamidobenzene). Base)] Vinyl coumarin. Further, 7-methoxy 8-[2-(2-hydroxy-5-(indolylmethyl)aminophenyl)]vinylcoumarin (Compound 23) was hydrolyzed according to the method of Example 14. Mass Spectrum: Μ/Ζ [Μ+1] + , 324. Example 23 Preparation of 7-Methoxy-8-[2-(2-hydroxy-5-(indolyl)aminophenyl)]vinylcoumarin (Compound 24)
按照实施例 1方法， 以 4一羟基一（Ν—乙基）乙酰苯胺代替苯制备化合物 7—甲氧基 一 8— [2—（2-羟基一 5—（Ν—乙基）乙酰氨基苯基）]乙烯基香豆素。再按照实施例 14 方 法水解制备 7—甲氧基一 8— [2—（2-羟基一 5—（Ν—乙基）氨基苯基）]乙烯基香豆素（化 合物 24)。 质谱： Μ/Ζ [Μ+1] +， 338。 实施例 24 制备 7-甲氧基一 8— [2- (2-甲基苯基) ]乙烯基香豆素 （化合物 3 ) According to the method of Example 1, 4-hydroxy-(indolyl)acetanilide was used instead of benzene to prepare compound 7-methoxy-8-[2-(2-hydroxy-5-(indolyl)acetamidobenzene). Base)] Vinyl coumarin. Further, 7-methoxy-8-[2-(2-hydroxy-5-(indolyl)aminophenyl)]vinylcoumarin (Compound 24) was hydrolyzed according to the method of Example 14. Mass Spectrum: Μ/Ζ [Μ+1] + , 338. Example 24 Preparation of 7-methoxy-8-[2-(2-methylphenyl)]vinylcoumarin (Compound 3)
7-甲氧基香豆素一 8—乙醛的制备
Preparation of 7-methoxycoumarin-8-acetaldehyde
二氯甲垸 600ml， 蛇床子素 15g， 搅拌下加入 NaI0420g， 室温搅拌 2h后， 搅拌下加入 饱和碳酸氢钠水溶液 100ml， 继续室温剧烈搅拌反应 18h， 分出有机层， 回收溶剂至干得 到 7-甲氧基香豆素一 8—乙醛 8. lg。 Dichloromethane 600ml, osthole 15g, add NaI0 4 20g with stirring, stir at room temperature for 2h, add 100ml of saturated sodium bicarbonate solution with stirring, continue stirring at room temperature for 18h, separate the organic layer, recover the solvent to dry 7-methoxycoumarin-8-acetaldehyde 8. lg.
7—甲氧基一 8— [2—羟基一 2— (2-甲基苯基) ]乙基香豆素的制备 Preparation of 7-methoxy- 8-[2-hydroxy-2-(2-methylphenyl)]ethylcoumarin
冰水冷却， 加入无水 THF 200mL, 镁屑 3g， 2—溴甲苯 20g， 剧烈搅拌下， 催化量碘， 反应开始后， 慢慢加热回流反应至镁屑几乎消失为止， 约需 2h， 冷至室温， 慢速滴加 7- 甲氧基香豆素一 8—乙醛 25g溶于无水 THF lOOmL的溶液， 加毕， 继续搅拌回流反应 3h。 蒸 除 THF， 冰水冷却下， 向残余物中加入水 lOOOm 以 3%硫酸调 pH6〜7， 二氯甲垸 200mL提取 3次。 合并有机层， 饱和盐水洗， 无水硫酸钠干燥， 减压蒸除溶剂， 得 7—甲氧基一 8— [2 一羟基一 2— (2-甲基苯基） ]乙基香豆素 23g。 Cool with ice water, add 200 mL of anhydrous THF, 3 g of magnesium powder, 20 g of 2-bromotoluene, and catalyze the amount of iodine under vigorous stirring. After the reaction starts, slowly heat and reflux until the magnesium chips almost disappear. It takes about 2 hours and is cooled to At room temperature, a solution of 7-methoxycoumarin-8-acetaldehyde 25 g dissolved in anhydrous THF 100 mL was added dropwise, and the reaction was continued for 3 h with stirring. The THF was distilled off, and ice water was added thereto, and water was added to the residue, and the mixture was adjusted to pH 6 to 7 with 3% sulfuric acid and 200 mL of dichloromethane. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated. 23g.
7—甲氧基一 8— [2- (2-甲基苯基) ]乙烯基香豆素的制备
Preparation of 7-methoxy-8-[2-(2-methylphenyl)]vinylcoumarin
7—甲氧基一 8— [2—羟基一 2—（2—甲基苯基）]乙基香豆素 2g， 冰醋酸 150ml， 无水 乙酸钠 5g， 90〜100°C搅拌反应 2h， 反应完毕， 减压回收溶剂至干， 用冰水洗涤得到 7— 甲氧基一 8— [2—（2—甲基苯基）]乙烯基香豆素（化合物 3 ) 1. 5g。质谱： M/Z [M+1] + , 293。 实施例 25 制备 7-甲氧基一 8— [2- (4-甲氧基苯基) ]乙烯基香豆素 （化合物 7 ) 7-methoxy-8-[2-hydroxy-2-(2-methylphenyl)]ethylcoumarin 2g, glacial acetic acid 150ml, anhydrous sodium acetate 5g, stirred at 90~100 °C for 2h, After completion of the reaction, the solvent was evaporated to dryness under reduced pressure and washed with ice water to give <RTI ID=0.0>> Mass Spectrum: M/Z [M+1] + , 293. Example 25 Preparation of 7-Methoxy-8-[2-(4-methoxyphenyl)]vinylcoumarin (Compound 7)
按照实施例 24方法，以 4一溴苯甲醚代替 2—溴甲苯制备化合物 7。质谱： M/Z [M+1] +,Compound 7 was prepared by the procedure of Example 24, substituting 4-bromoanisole for 2-bromotoluene. Mass spectrometry: M/Z [M+1] + ,
309。 实施例 26 制备 7—甲氧基一 8— [2—羟基一 2—（4一羟基苯基) ]乙基香豆素磷酸 (化合物 25) 309. Example 26 Preparation of 7-methoxy-8-[2-hydroxy-2-(4-hydroxyphenyl)]ethylcoumarin phosphoric acid (Compound 25)
无水吡啶 100ml， 加入双一 （0—三氯乙基） 磷酰氯 12g， 搅拌下加入 7—甲氧基一 8 一 [2—羟基一 2—（4一羟基苯基) ]乙基香豆素 8g， 60〜70°C反应 4h， 真空浓缩至干， 用二 氯甲垸 200ml溶解， 有机层分别用浠盐酸， 水和浠碳酸氢钠溶液洗涤， 回收溶剂至干得油 状物， 用吡啶 100ml溶解， 搅拌下慢慢滴加乙酸 10ml， 滴加完毕， 加入锌粉 3g， 50〜60 ！搅拌反应 20h， 冷却室温， 用硅藻土 100g过滤， 滤饼用甲醇洗涤， 回收溶剂至干， 加
二氯甲垸 200ml溶解， 分别用水、 浠盐酸和浠碳酸氢钠洗涤， 回收溶剂得到化合物 25。 质谱： M/Z [M+1] +, 375； [M+Na] +， 397。 100 ml of anhydrous pyridine, adding 12 g of bis(0-trichloroethyl)phosphoryl chloride, and adding 7-methoxy-8-[2-hydroxy-2-(4-hydroxyphenyl)]ethylcoumarin with stirring 8g, reacted at 60~70 °C for 4h, concentrated to dryness in vacuo, dissolved in 200ml of dichloromethane, the organic layer was washed with hydrazine hydrochloride, water and sodium hydrogen carbonate solution respectively, and the solvent was recovered to dry oil. Dissolve 100ml, slowly add 10ml of acetic acid with stirring, add dropwise, add zinc powder 3g, 50~60! Stir the reaction for 20 h, cool to room temperature, filter with 100 g of celite, filter cake washed with methanol, recover solvent to dry, add Dichloromethane 200 ml was dissolved, washed with water, hydrazine hydrochloride and hydrazine sodium hydrogencarbonate, respectively, and the solvent was recovered to give compound 25. Mass Spectrum: M/Z [M+1] + , 375; [M+Na]+, 397.
实施例 27 制备 7—甲氧基一 8— [2—羟基一 2—（4一羟基苯基) ]乙基香豆素磷酸钠 (化合 物 26) Example 27 Preparation of 7-methoxy-8-[2-hydroxy-2-(4-hydroxyphenyl)]ethylcoumarin sodium phosphate (Compound 26)
7—甲氧基一 8— [2—羟基一 2—（4一羟基苯基）]乙基香豆素磷酸 （化合物 25 ) 5g, 甲 醇 50ml， 蒸馏水 50ml， 搅拌下滴加 2N氢氧化钠调节溶液 pH7〜7. 5， 溶液真空浓缩至干， 加 70 %甲醇水溶液 20ml， 冷却结晶， 过滤得到化合物 26。 质谱： M飾 +1] +， 375； [M+ Na] +， 397。
7-methoxy-8-[2-hydroxy-2-(4-hydroxyphenyl)]ethylcoumarin phosphoric acid (compound 25) 5g, methanol 50ml, distilled water 50ml, 2N sodium hydroxide added dropwise with stirring The solution was pH 7~7. 5, the solution was concentrated to dryness in vacuo, and then 20 ml of 70% aqueous methanol. Mass Spectrum: M +1] +, 375; [M+ Na] +, 397.
Claims
1.本发明公开了下述通式 （I ) 化合物或其药学上可接受的盐: 1. The present invention discloses a compound of the following formula (I) or a pharmaceutically acceptable salt thereof:
式 I Formula I
其中， Rl、 R2、 R3、 R4或 R5分别代表氢、氨基或者取代氨基、 垸基或取代垸基或 0M， 其中 M为氢、 垸基或者取代垸基或磷酸基及其盐。 Wherein R1, R2, R3, R4 or R5 represents hydrogen, an amino group or a substituted amino group, a fluorenyl group or a substituted fluorenyl group or 0M, respectively, wherein M is hydrogen, a fluorenyl group or a substituted fluorenyl group or a phosphate group and a salt thereof.
2. 权利要求 1所述的化合物制备方法， 该方法通过下述方法制得： 2. A method of preparing a compound according to claim 1, which is obtained by the following method:
其中， Rl、 R2、 R3、 R4或 R5分别代表氢、 氨基或者取代氨基、 垸基或取代垸基或 OM， 其中 M为氢、 垸基或者取代垸基或磷酸基及其盐。
Wherein R1, R2, R3, R4 or R5 represents hydrogen, amino or substituted amino, fluorenyl or substituted fluorenyl or OM, respectively, wherein M is hydrogen, fluorenyl or substituted fluorenyl or phosphoryl and salts thereof.
3.权利要求 1所述的化合物制备方法， 该方法还通过下述方法制得: 3. The method of preparing a compound according to claim 1, which is also obtained by the following method:
其中， Rl、 R2、 R3、 R4或 R5分别代表氢、氨基或者取代氨基、 垸基或取代垸基或 0M， 其中 M为氢、 垸基或者取代垸基或磷酸基及其盐。 Wherein R1, R2, R3, R4 or R5 represents hydrogen, an amino group or a substituted amino group, a fluorenyl group or a substituted fluorenyl group or 0M, respectively, wherein M is hydrogen, a fluorenyl group or a substituted fluorenyl group or a phosphate group and a salt thereof.
4.权利要求 1、 2或 3所述的化合物或其药学上可接受的盐在制备治疗抗肿瘤药物中 的应用。 The use of the compound according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of an antitumor.
5.权利要求 1、 2或 3所述的化合物或其药学上可接受的盐在制备治疗血管性视网膜 病变药物中的应用。
5. Use of a compound according to claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of vascular retinopathy.
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| CN2007101318030A CN101121706B (en) | 2007-09-18 | 2007-09-18 | Coumarin derivatives, preparation method and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408530A (en) * | 2013-08-26 | 2013-11-27 | 中国人民解放军第三军医大学 | Coumarin skeleton polycyclic compound with biological activity as well as preparation method and use thereof |
| WO2018236138A1 (en) * | 2017-06-20 | 2018-12-27 | 한국식품연구원 | Composition for prevention, alleviation, reduction, or treatment of retinal disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109985036A (en) * | 2018-06-13 | 2019-07-09 | 上海交通大学医学院附属第九人民医院 | The new application of Osthole and its application |
| CN112062743B (en) * | 2020-08-19 | 2023-01-10 | 浙江工业大学 | Resveratrol derivative and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2001017984A1 (en) * | 1999-09-03 | 2001-03-15 | Indena S.P.A. | Chalcone coumarins |
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| DE4136900C1 (en) * | 1991-11-09 | 1993-07-29 | Schaper & Bruemmer Gmbh & Co Kg, 3320 Salzgitter, De |
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|---|---|---|---|---|
| WO2001017984A1 (en) * | 1999-09-03 | 2001-03-15 | Indena S.P.A. | Chalcone coumarins |
Non-Patent Citations (3)
| Title |
|---|
| CHAVEZ. D. ET AL.: "Novel stilbenes isolated from the root bark of Ekebergia besiguelensis.", TETRAHEDRON LETTERS, vol. 42, no. 22, 2001, pages 3685 - 3688, XP004249059, DOI: doi:10.1016/S0040-4039(01)00560-3 * |
| MOORTHY, JARUGU NARASIMHA ET AL.: "Cis->trans and trans->cis isomerizations of styrylcoumarins in the solid state. Importance of location of free volume in crystal lattices.", PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES, vol. 5, 2006, pages 903 - 913 * |
| SEO. E. K. ET AL.: "5-(4-hydroxyphenethenyl)-4,7-dimethoxycoumarin, a new constituent of Monotes engleri.", PLANTA MEDICA, vol. 66, no. 2, 2000, pages 182 - 184 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408530A (en) * | 2013-08-26 | 2013-11-27 | 中国人民解放军第三军医大学 | Coumarin skeleton polycyclic compound with biological activity as well as preparation method and use thereof |
| CN103408530B (en) * | 2013-08-26 | 2015-05-27 | 中国人民解放军第三军医大学 | Coumarin skeleton polycyclic compound with biological activity as well as preparation method and use thereof |
| WO2018236138A1 (en) * | 2017-06-20 | 2018-12-27 | 한국식품연구원 | Composition for prevention, alleviation, reduction, or treatment of retinal disease |
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| CN101121706A (en) | 2008-02-13 |
| CN101121706B (en) | 2010-11-24 |
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