CN108586535A - 含喜树碱结构的磷脂类似物、制备方法及用途 - Google Patents
含喜树碱结构的磷脂类似物、制备方法及用途 Download PDFInfo
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- CN108586535A CN108586535A CN201810712340.5A CN201810712340A CN108586535A CN 108586535 A CN108586535 A CN 108586535A CN 201810712340 A CN201810712340 A CN 201810712340A CN 108586535 A CN108586535 A CN 108586535A
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- camptothecine
- phospholipid analogues
- coupling agent
- catalyst
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了式（1）所示的含喜树碱结构的磷脂类似物，本发明还提供了该磷脂类似物的制备方法及在制备抗肿瘤药物上的用途。
Description
技术领域
本发明涉及药物化学和治疗学领域，具体涉及含喜树碱结构的脑磷脂类似物、制备方法及其作为抗肿瘤药物的用途。
背景技术
喜树碱(Camptothecin，CPT) 是从我国特有植物喜树中提取得到的生物碱。在早期的体外活性筛选中，喜树碱表现出较强的抗肿瘤活性，对多种实体肿瘤和白血病具有明显的抑制作用，但喜树碱水溶性差、毒性强，因此限制了它在肿瘤治疗上的应用。1985年Hsiang Y.H. 等发现喜树碱是通过抑制拓扑异构酶I 发挥细胞毒活性，又重新引起了人们的关注。许多研究者开始投入于喜树碱化学结构的修饰与改良，致力于改善其在人体内的吸收状况和增强治疗效果。目前为止，美国食品药品管理局已批准Topotecan 和Irinotecan 两种喜树碱衍生物上市用于治疗复发性卵巢癌、直肠/ 结肠癌。另有多种衍生物如9- 硝基喜树碱、9- 氨基喜树碱、CKD-602、DX-9815f、GI-147211 正在进行不同阶段的临床研究。喜树碱E 环结构中闭合的α- 羟基内酯环是其保持抗肿瘤活性的必需结构，但此α- 羟基内酯环在人体内易水解开环形成羧酸盐结构，这种开环形式易与人血清蛋白结合而使其丧失抗肿瘤活性。更为严重的是，开环形式的钠盐经肾脏代谢后对泌尿系统和消化系统有极大的毒副作用。另外，喜树碱类衍生物水难溶性的问题，至今尚未解决，严重地阻碍着喜树碱类衍生物在临床中的推广应用。
喜树碱衍生物的制备方法研究较多，以下给出部分文献作为参考。
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磷脂是重要的两亲物质，磷脂分子会在水中自然形成多层微囊，每层均为脂质的双分子层，微囊中央与各层之间被水相隔开，由于它的结构类似生物膜，容易通过细胞膜进入组织细胞。磷酯酰甘油磷酸胆碱（即卵磷脂）是磷脂的一种，可用作抗氧剂。也用于医疗上。
通过化学键合作用形成喜树碱-磷酯酰甘油磷酸胆碱复合物。该复合物既能通过增加位阻来降低喜树碱E 环结构中闭合的α- 羟基内酯环的水解程度，又可通过自组装制成相应的脂质体药物传递系统，进而解决喜树碱毒性强、水溶性差的问题。
发明内容
本发明的一个目的是提供一类新型的抗肿瘤活性强、生物利用度显著提高的含喜树碱结构的磷脂类似物。
本发明的另一个目的是提供该类含喜树碱结构的磷脂类似物的制备方法。
本发明的再一个目的是提供该类含喜树碱结构的磷脂类似物作为抗肿瘤药物的应用。
为了实现上述目的，本发明提供的是具有式（1）所示的含喜树碱结构的磷脂类似物。
（1）
本发明提供了含喜树碱结构的磷脂类似物的方法，包括如下步骤：
(1) 在干燥的有机溶剂中，喜树碱与3,3'-二硫代二丙酸在偶联剂及催化剂的作用下进行酯化反应，得到具有式(2) 结构的中间体a;
(2)
(2)中间体a在偶联剂及催化剂的作用下与1-硬脂酰-Sn-丙三醇-3-磷酸胆碱反应，制得含喜树碱结构的磷脂类似物。
其中，制备卵磷脂类似物的方法中所述的有机溶剂是二氯甲烷、二甲基亚砜和N，N- 二甲基甲酰胺；所述的偶联剂是N，N- 二环己基碳二亚胺(DCC)、N，N- 羰基二咪唑(CDI)和1-(3- 二甲氨基丙基)-3- 乙基碳二亚胺盐酸盐(EDC.HCl) ；所述的催化剂是吡啶和4-二甲氨基吡啶(DMAP)。
本发明还涉及含有作为活性成分的本发明化合物及药效学上可接受载体的各种制剂。
“药效学上可接受载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，他们适合于人使用，而且有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺合，而不明显降低化合物的药效。药效学上可接受的载体部分例子有糖( 如葡萄糖、蔗糖、乳糖等)，淀粉( 如玉米淀粉、马铃薯淀粉等)，纤维素及其衍生物( 如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)，明胶，滑石，固体润滑剂( 如硬脂酸、硬脂酸镁)，硫酸钙，植物油( 如油豆、芝麻油、花生油、橄榄油等)，多元醇( 如丙二醇、甘油、甘露醇、山梨醇等)，乳化剂( 如吐温)、润滑剂( 如十二烷基硫酸钠)，着色剂，调味剂，稳定剂，抗氧化剂，防腐剂，无热原水等。
本发明还涉及本发明所述的化合物制备抗肿瘤药物中的应用。
体外活性筛选实验表明所述的含喜树碱结构的磷脂类似物具有明显的抗肿瘤作用及良好的剂量依赖关系。以人卵巢癌细胞系HXB1309H为受试细胞株，测定了含喜树碱结构的磷脂类似物的半数抑制浓度（IC50）为5.718微摩尔/升。
具体实施方式
下面结合实施例对本发明作进一步详细描阐述：
具有式（1）所示的含喜树碱结构的磷脂类似物。
（1）
本发明提供了含喜树碱结构的磷脂类似物的方法，包括如下步骤：
(1) 在干燥的有机溶剂中，喜树碱与3,3'-二硫代二丙酸在偶联剂及催化剂的作用下进行酯化反应，得到具有式(2) 结构的中间体a;
(2)
(2)中间体a在偶联剂及催化剂的作用下与1-硬脂酰-Sn-丙三醇-3-磷酸胆碱反应，制得含喜树碱结构的磷脂类似物。
其中，制备卵磷脂类似物的方法中所述的有机溶剂是二氯甲烷、二甲基亚砜和N，N- 二甲基甲酰胺；所述的偶联剂是N，N- 二环己基碳二亚胺(DCC)、N，N- 羰基二咪唑(CDI)和1-(3- 二甲氨基丙基)-3- 乙基碳二亚胺盐酸盐(EDC.HCl) ；所述的催化剂是吡啶和4-二甲氨基吡啶(DMAP)。
本发明还涉及含有作为活性成分的本发明化合物及药效学上可接受载体的各种制剂。
“药效学上可接受载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，他们适合于人使用，而且有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺合，而不明显降低化合物的药效。药效学上可接受的载体部分例子有糖( 如葡萄糖、蔗糖、乳糖等)，淀粉( 如玉米淀粉、马铃薯淀粉等)，纤维素及其衍生物( 如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)，明胶，滑石，固体润滑剂( 如硬脂酸、硬脂酸镁)，硫酸钙，植物油( 如油豆、芝麻油、花生油、橄榄油等)，多元醇( 如丙二醇、甘油、甘露醇、山梨醇等)，乳化剂( 如吐温)、润滑剂( 如十二烷基硫酸钠)，着色剂，调味剂，稳定剂，抗氧化剂，防腐剂，无热原水等。
本发明还涉及本发明所述的化合物制备抗肿瘤药物中的应用。
实施例1 制备喜树碱-20-O-（3,3'- 二硫代二丙酰）单酯
将2.1克（0.01摩尔）3,3'-二硫代二丙酸溶于300毫升二氯甲烷中，依次加入1克二甲氨基吡啶、3.5克（0.01摩尔）喜树碱、3克N,N'-二环己基碳酰亚胺，在室温下搅拌24小时，过滤除去沉淀，滤液减压浓缩除去溶剂，将浓缩剩余物用硅胶柱层析（二氯甲烷：甲醇=20：1）,得浅黄色喜树碱-20-O-（3,3'- 二硫代二丙酰）单酯3.35克，收率62%。
1HNMR(300MHz，DMSO-d6，ppm) ：δ0.96(3H，t，H-19)，2.10(2H，m，H-18)，2.58-2.72(4H，m，-OOCCH2 CH2S-)，2.87-2.99(4H，m，-OOCCH2CH2 S-),5.11(2H，s，H-5)，5.50(2H，s，H-17)，6.89(1H，d，N-H)，7.14(H，s，H-14)，7.72(1H，q，H-10)，7.87(H，t，H-11)，8.00(1H，d，H-12)，8.14(1H，d，H-9)，8.42(1H，t，N-H)，8.65(1H，s，H-7)。ESIMS m/z ：539.3(M-1)-。
实施例2 制备1-硬脂酰-2-（喜树碱-20-O-（3,3'- 二硫代二丙酰）单酯）丙三醇-3-磷酸胆碱
。
将0.540克（0.001摩尔）喜树碱-20-O-（3,3'- 二硫代二丙酰）单酯溶于200毫升二氯甲烷中，加入0.5克1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐，0.1克4-二甲氨基吡啶，室温下，搅拌3小时后加入0.523克（0.001摩尔）1-硬脂酰-Sn-丙三醇-3-磷酸胆碱，室温下，搅拌72小时，将反应液倒入500毫升冰水中，过滤，在50℃下，真空干燥滤饼，将滤饼用硅胶柱层析（甲醇：氯仿：水=25：65:2）,得黄色1-硬脂酰-2-（喜树碱-20-O-（3,3'- 二硫代二丙酰）单酯）丙三醇-3-磷酸胆碱0.21克（即磷脂类似物），收率20%。
1HNMR(300MHz，DMSO-d6，ppm) ：2.58-2.72(4H，m，-OOCCH2 CH2S-)，2.87-2.99(4H，m，-OOCCH2CH2 S-),3.23(12H, m,-NCH3,-CH2-N-), 3.56-4.17 (4H m, -OC2H4N-),5.13(2H，s，H-5)，5.55(2H，s，H-17)，6.89(1H，d，N-H)，7.14(H，s，H-14)，7.72(1H，q，H-10)，7.87(H，t，H-11)，8.00(1H，d，H-12)，8.14(1H，d，H-9)，8.42(1H，t，N-H)，8.65(1H，s，H-7)。
实例3 制备磷脂类似物自组装脂质体
将0.05克1-硬脂酰-2-（喜树碱-20-O-（3,3'- 二硫代二丙酰）单酯）丙三醇-3-磷酸胆碱溶于5毫升甲醇中，超声波作用下，一次性加入25毫升蒸馏水，超声10分钟后，快速吹除甲醇，剩余物经冷冻干燥制得纳米级别微粒（粒径≤200nm），即为含卵磷脂类似物自组装脂质体。
Claims (6)
1.式（1）所示的含喜树碱结构的磷脂类似物
（1）。
2.制备权利要求1所述的含喜树碱结构的磷脂类似物的方法，包括如下步骤：
(1) 在干燥的有机溶剂中，喜树碱与3,3'-二硫代二丙酸在偶联剂及催化剂的作用下进行酯化反应，得到具有式(2) 结构的中间体a;
（2）
(2)中间体a在偶联剂及催化剂的作用下与1-硬脂酰-Sn-丙三醇-3-磷酸胆碱反应，制得含喜树碱结构的磷脂类似物。
3.按照权利要求2 所述的制备卵磷脂类似物的方法，其特征在于所述的有机溶剂是二氯甲烷、二甲基亚砜和N，N- 二甲基甲酰胺；所述的偶联剂是N，N- 二环己基碳二亚胺(DCC)、N，N- 羰基二咪唑(CDI) 和1-(3- 二甲氨基丙基)-3- 乙基碳二亚胺盐酸盐(EDC.HCl) ；所述的催化剂是吡啶和4- 二甲氨基吡啶(DMAP)。
4.一种药物组合物，含有权利要求1所述的任一化合物，以及药效学上可接受的载体。
5.根据权利要求4的药物组合物，其特征在于所述的药物组合物可以是片剂、胶囊、丸剂、注射剂、缓释制剂。
6.权利要求1所述的卵磷脂类似物在制备抗肿瘤药物中的应用。
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