CN107236004B - 二氢杨梅素环磷酰胺衍生物及其制备方法和应用 - Google Patents
二氢杨梅素环磷酰胺衍生物及其制备方法和应用 Download PDFInfo
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- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
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Abstract
本发明属于生物制药技术领域，具体涉及一种二氢杨梅素环磷酰胺衍生物或其药学可接受的水合物，包括其立体异构体或互变异构体，及其制备方法和应用。本发明在二氢杨梅素结构中引入了环磷酰胺基团，合成了结构新颖的二氢杨梅素衍生物，该类化合物具有抗肿瘤活性。
Description
技术领域
本发明涉及二氢杨梅素环磷酰胺衍生物，及其在制药中的应用，属于医药技术领域。
背景技术
文献报道，二氢杨梅素对白血病细胞HL-60、 K562以及肝癌细胞Bel-7404、腹水型肝癌H22瘤株、人鼻咽癌HK-1和人乳腺癌MCF-7细胞的增殖均有显著的抑制作用，体内对小鼠移植性B16黑色素瘤的生长也具有显著的抑制作用，此外还有清除自由基、镇咳祛痰、降脂保肝、抗血栓、抗氧化及降血糖等作用。二氢杨梅素在藤茶等植物中含量高，来源丰富，且具有多方面的显著功效，以其为先导物，克服其溶解性和稳定性差的缺点，发现疗效更好的新药，是新药研发的一个方向。
环磷酰胺为氮芥与磷酰胺基结合而成的化合物，即能非特异性杀伤抗原敏感性小淋巴细胞，又能抑制细胞增殖，限制其转化为免疫母细胞，可用于治疗各种自身免疫性疾病。临床上用于治疗白血病，淋巴瘤和实体瘤等恶性病，但它具有膀胱毒性，需要进一步结构修饰，降低毒性，提高疗效。
本发明将环磷酰胺结构引入二氢杨梅素结构中，以期获得抗肿瘤活性高、毒性低的药物。
发明内容
本发明的目的在于提供一种二氢杨梅素环磷酰胺衍生物，其具有抗癌作用。
本发明的另一目的在于提供上述二氢杨梅素环磷酰胺衍生物的制备方法。
本发明的再一目的在于提供上述二氢杨梅素环磷酰胺衍生物的用途。
以下对本发明进行详细描述。
本发明提供的二氢杨梅素环磷酰胺衍生物或其药学可接受的水合物，包括其立体异构体或互变异构体，结构如下所示：
式中，R各自独立为H，酰基，甲基。
所述的二氢杨梅素环磷酰胺衍生物具体结构实例如下：
本发明还提供了上述化合物的制备方法：
式中，R各自独立为H，酰基，甲基。
本发明的二氢杨梅素环磷酰胺衍生物或其药学可接受的水合物，包括其立体异构体或互变异构体，具有抗肿瘤作用。
通过以下实施例进一步举例说明本发明，但应注意本发明的范围并不受这些实施例的任何限制。
具体实施方式
实施例1
中间体IIa的制备
N2下，取二氢杨梅素200mg (0.62 mmol)，溶于7mL无水DMF溶液中，加入无水552mg(2.5 mmol) K2CO3，缓慢加入383mg (2.7 mmol)碘甲烷，40℃反应24h，停止反应，加1mL醋酸，过滤，减压蒸干，回收溶剂，硅胶柱层析纯化（V石油醚：V乙酸乙酯 = 6:1），得到7,3’,4’,5’-四甲氧基二氢杨梅素中间体（IIa）。收率26.2%。
中间体IIb的制备：
N2下，取二氢杨梅素200mg (0.62 mmol)，溶于7mL无水DMF溶液中，加入无水690mg(3.1 mmol) K2CO3，缓慢加入710mg (3.1 mmol)碘甲烷，40℃反应24h，停止反应，加1mL醋酸，过滤，减压蒸干，回收溶剂，硅胶柱层析纯化（V石油醚：V乙酸乙酯 = 6:1），得到3,7,3’,4’,5’-五甲氧基二氢杨梅素中间体（IIb）。收率27.0%。
中间体IIc的制备：
N2下，取二氢杨梅素200mg (0.62 mmol)，溶于7mL无水DMF溶液中，加入无水828mg(3.8 mmol) K2CO3，缓慢加入852mg (3.8 mmol)碘甲烷，其它操作同上，得到3,7,9,3’,4’,5’-六甲氧基二氢杨梅素中间体（IIc）。收率36.2%。
中间体IId的制备：
N2下，取二氢杨梅素200mg (0.62 mmol)，加入5mL醋酐中，超声下混匀，避光放置2天，倒入冰水中研磨，过滤，干燥，乙酸乙酯-乙醇重结晶，得到3,7,3’,4’,5’-五乙酰基二氢杨梅素中间体（IId），收率73%，m.p. 163-165℃。
中间体IIe的制备：
N2下，取二氢杨梅素200mg (0.62 mmol)，加入5mL醋酐中，超声下混匀，避光放置2天，倒入冰水中研磨，过滤，干燥，乙酸乙酯-乙醇重结晶，得到3,5，7,3’,4’,5’-六乙酰基二氢杨梅素中间体（IIe），收率68%，m.p. 173-175℃。
中间体IIf的制备：
N2保护下，将320 mg (1.0 mmol)二氢杨梅素溶于5mLDMF中，加入5滴吡啶和112mg (1.1 mmol)Ac2O，室温反应10h，减压蒸除溶剂，柱层析纯化（V氯仿：V乙醇= 6:1,4:1,2:1梯度淋洗），得7-乙酰基二氢杨梅素。
N2保护下，将362 mg (1.0 mmol)7-乙酰基二氢杨梅素溶于5mLDMF中，加入625 mg(4.4 mmol)MeI 和607mg (4.4 mmol)K2CO3, 室温反应过夜，过滤，加入10mL浓度为30%的乙二胺甲醇溶液，40℃反应8h，减压蒸干，柱层析纯化（V氯仿：V乙醇= 6:1,4:1,2:1梯度淋洗），得3,3’,4’,5’-四甲氧基二氢杨梅素（中间体IIf）,收率33%。
中间体IIg的制备：
N2保护下，称取1.6g（5mmol）二氢杨梅素（含量98%)置于50mL的三角瓶中，然后依次加入15ml醋酸酐和1.2g硼酸，混匀，避光放置3天，倒入冰水中研磨，有黄色硼酸络合物析出，过滤，将所得黄色固体物加入40mL含有10%的HC1溶液，于60℃反应30min，除去硼酸，有黄白色固体生成，过滤，用水淋洗至中性，收集固体，干燥后即得粗品。用EtOH重结晶，得白色晶体，即二氢杨梅素四乙酰化产物(中间体IIg)，产率89%。m.p.205-206℃。
实施例2
中间体IIIa-g和8-硝基二氢杨梅素的制备:
N2下，分别将0.2mL70%HNO3与10mL醋酸混合，65℃分别滴加0.5mmol中间体IIa-g/250mL醋酸的溶液，滴毕，反应2h，冷却，反应液倒入200mL冰水中，搅拌，析出固体，过滤，水洗，乙醇重结晶，分别得到IIIa，收率70%；IIIb，收率76%；IIIc，收率77%；IIId，收率79%；IIIe，收率81%；IIIf，收率78%；IIIg，收率71%。
用0.5mmol二氢杨梅素代替0.5mmol中间体IIa-g，其它操作不变，得到8-硝基二氢杨梅素，收率67%。
实施例3
中间体IVa-g和8-氨基二氢杨梅素的制备:
高压釜中，分别将0.5mmol的IIIa-g加入到100mL乙醇中，分别加入30mg10%的Pd-C，用N2置换空气后，通入H2，80℃反应2h，冷却，过滤，旋蒸出乙醇，硅胶柱层析纯化，分别得到IVa，收率87%；IVa，收率87%；IVb，收率89%；IVc，收率89%；IVd，收率90%；IVe，收率91%；IVf，收率87%；IVg，收率89%。
用0.5mmol8-硝基二氢杨梅素代替0.5mmol中间体IIIa-g，其它操作不变，得到8-氨基二氢杨梅素，收率92%。
实施例4
中间体Va-g和8-（3-羟基丙氨基）二氢杨梅素的制备:
N2下，分别将0.5mmol的IVa-g溶于50mL丙酮，分别加入56.4mg(0.6mmol)的3-氯丙醇和82.8mg(0.6mmol)的K2CO3，回流反应7h，冷却，过滤，蒸除溶剂，硅胶柱层析纯化，分别得到Va，收率67%；Vb，收率71%；Vc，收率69%；Vd，收率72%；Ve，收率67%；Vf，收率65%；Vg，收率69%。
用0.5mmol的8-氨基二氢杨梅素代替0.5mmol的IVa-g，得到8-（3-羟基丙氨基）二氢杨梅素，收率70%。
实施例5
化合物（1-8）的制备:
N2下，分别将0.5mmol的Va-g或8-（3-羟基丙氨基）二氢杨梅素溶于50mL丙酮，冷却至0℃，分别加入141mg(0.55mmol)氮芥磷酰二氯和111mg(1.1mmol)Et3N，自然升至室温，反应8小时，过滤，滤液浓缩，柱层析纯化，分别得化合物（1-8）。
化合物（1）：收率80%；ESI-MS (m/z): 578 [M]+；1H NMR（300MHz，DMSO-d6）δ 1.86(m, 2H), 3.15 (m, 2H), 3.34 (m, 4H), 3.68 (m, 4H),4.42 (d, J = 11Hz, 1H),4.45 (m, 2H),4.93 (d, J = 11Hz, 1H), 5.57 (s, 1H),5.87 (s, 1H), 7.40 (s, 2H),8.19 (s, 1H), 8.90 (s, 2H), 10.07 (s, 1H), 11.85 (s, 1H)。
化合物（2）：收率84%；ESI-MS (m/z): 634 [M]+；1H NMR（300MHz，DMSO-d6）δ 1.85(m, 2H), 3.16 (m, 2H), 3.34 (m, 4H), 3.68 (m, 4H), 3.91 (s, 9H), 3.94 (s,3H),4.42 (d, J = 11Hz, 1H), 4.45 (m, 2H),4.93 (d, J = 11Hz, 1H), 5.56 (s,1H),5.86 (s, 1H), 7.40 (s, 2H), 11.85 (s, 1H)。
化合物（3）：收率83%；ESI-MS (m/z): 648 [M]+；1H NMR（300MHz，DMSO-d6）δ 1.86(m, 2H), 3.15 (m, 2H), 3.35 (m, 4H), 3.44 (s, 3H), 3.68 (m, 4H), 3.91 (s,9H), 3.94 (s, 3H),4.42 (d, J = 11Hz, 1H), 4.45 (m, 2H),4.93 (d, J = 11Hz,1H), 5.86 (s, 1H), 7.40 (s, 2H), 11.85 (s, 1H)。
化合物（4）：收率81%；ESI-MS (m/z): 662 [M]+；1H NMR（300MHz，DMSO-d6）δ 1.86(m, 2H), 3.16 (m, 2H), 3.35 (m, 4H), 3.44 (s, 3H), 3.68 (m, 4H), 3.91 (s,12H), 3.94 (s, 3H),4.42 (d, J = 11Hz, 1H), 4.45 (m, 2H),4.93 (d, J = 11Hz,1H), 5.86 (s, 1H), 7.40 (s, 2H)。
化合物（5）：收率81%；ESI-MS (m/z): 788 [M]+；1H NMR（300MHz，DMSO-d6）δ 1.85(m, 2H), 2.28 (s, 6H), 2.30 (s, 6H), 2.35 (s, 3H), 3.15 (m, 2H), 3.35 (m,4H), 3.68 (m, 4H), 5.82 (m, 1H), 4.45 (m, 2H),5.93 (m, 1H), 6.96 (s, 1H),7.40 (s, 2H), 11.37 (s, 1H)。
化合物（6）：收率85%；ESI-MS (m/z): 830 [M]+；1H NMR（300MHz，DMSO-d6）δ 1.85(m, 2H), 2.28 (s, 6H), 2.30 (s, 6H), 2.35 (s, 6H), 3.15 (m, 2H), 3.35 (m,4H), 3.68 (m, 4H), 5.82 (m, 1H), 4.45 (m, 2H),5.93 (m, 1H), 6.96 (s, 1H),7.40 (s, 2H)。
化合物（7）：收率77%；ESI-MS (m/z): 634 [M]+；1H NMR（300MHz，DMSO-d6）δ 1.86(m, 2H), 3.16 (m, 2H), 3.35 (m, 4H), 3.44 (s, 3H), 3.68 (m, 4H), 3.91 (s,6H), 3.94 (s, 3H),4.42 (d, J = 11Hz, 1H), 4.45 (m, 2H),4.93 (d, J = 11Hz,1H), 5.86 (s, 1H), 7.40 (s, 2H), 10.02 (s, 1H) 11.85 (s, 1H)。
化合物（8）：收率76%；ESI-MS (m/z): 746 [M]+；1H NMR（300MHz，DMSO-d6）δ 1.85(m, 2H), 2.28 (s, 6H), 2.30 (s, 6H), 3.15 (m, 2H), 3.35 (m, 4H), 3.68 (m,4H), 5.82 (m, 1H), 4.45 (m, 2H),5.93 (m, 1H), 6.96 (s, 1H), 7.40 (s, 2H),10.01 (s, 1H) 11.85 (s, 1H)。
实施例6
分别将1mmol化合物（1-8）加入含水丙酮溶液中，搅拌2h，过滤，干燥，分别得到化合物（1-8）的一水合物。
实施例7
二氢杨梅素环磷酰胺衍生物抗肿瘤活性研究
化合物体外抗肿瘤活性用IC50值评定：将细胞按一定密度接种于含10体积% 小牛血清的RPMI1640培养基（内含适量青霉素、链霉素和谷氨酰胺）的96孔板中，5wt%CO2，37℃条件下培养24小时后，换用不同浓度授试药物（用PBS配制成1μg/mL工作液，使用时按需要用培养基稀释）的新鲜培养基，不同稀释浓度的阳性对照药5-氟尿嘧啶药液为阳性对照，每组设6个平行孔，继续培养48小时。取出96孔培养板，每孔加入20μL 5mg/mL的MTT，继续培养4小时。取出培养板，倒出培养基，每孔加入200μL DMSO，平板摇床震摇5分钟，待结晶溶解后，置酶联检测仪，于570nm波长下测定各孔的OD值。用Bliss法求出半数抑制浓度IC50。
二氢杨梅素环磷酰胺衍生物对HL60（白血病细胞）、MCF-7（人乳腺癌）、HeLa（人宫颈癌）、SGC-803（胃癌）和HepG2（肝癌）肿瘤细胞株的抑制活性如表1所示。结果显示，二氢杨梅素环磷酰胺衍生物具有好的抗癌活性。
Claims (1)
1.一种二氢杨梅素环磷酰胺衍生物，选自：
。
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| 藤茶的有效成分及药用价值研究进展;谭锦荣;《华夏医学》;20161231;第29卷(第5期);第158-161页 |
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