CN102649795B - 10-甲氧基喜树碱衍生物、制备方法和用途 - Google Patents
10-甲氧基喜树碱衍生物、制备方法和用途 Download PDFInfo
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- CN102649795B CN102649795B CN201110169681.0A CN201110169681A CN102649795B CN 102649795 B CN102649795 B CN 102649795B CN 201110169681 A CN201110169681 A CN 201110169681A CN 102649795 B CN102649795 B CN 102649795B
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- methoxycamptothecine
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- 238000002360 preparation method Methods 0.000 title abstract description 14
- KLFJSYOEEYWQMR-NRFANRHFSA-N 10-methoxycamptothecin Chemical class C1=C(OC)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 KLFJSYOEEYWQMR-NRFANRHFSA-N 0.000 claims description 28
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
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- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明提供式(1)所示的10-甲氧基喜树碱衍生物,式中,R选自氢、C1-6烷基、芳基取代C1-6烷基,R1选自氢、叔丁氧羰基取代氨基。本发明还提供了该类衍生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,具体涉及新的10-甲氧基喜树碱衍生物、其制备方法及用途。
背景技术
喜树碱(Camptothecin,CPT)是1966年由Wall等人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、毒副作用强, 因此限制了它在肿瘤治疗上的应用。10-甲氧基喜树碱(10-methoxycamptothecin)是喜树碱的天然衍生物,抗肿瘤活性优于喜树碱,但毒性也更强。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(FDA)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。
10-甲氧基喜树碱化学结构式
发明内容
本发明的一个目的是提供新的高效低毒的10-甲氧基喜树碱衍生物。
本发明的另一个目的是提供该类10-甲氧基喜树碱衍生物的制备方法。
本发明的再一个目的是提供该类10-甲氧基喜树碱衍生物及其组合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通式(1)的10-甲氧基喜树碱衍生物。
式中,R选自氢、C1-6烷基、芳基取代C1-6烷基,R1选自氢、叔丁氧羰基取代氨基。
其中,所述的喜树碱衍生物,当R1选自氢时,R选自:
-CH3
其中,所述的喜树碱衍生物,当R1选自叔丁氧羰基取代氨基时,R是:
-H -CH3
尤其是,所述的喜树碱衍生物,当R1选自叔丁氧羰基取代氨基时,R是:
-CH3
本发明提供的所述的10-甲氧基喜树碱衍生物的制备方法,10-甲氧基喜树碱与N-叔丁氧羰基氨基酸和羧酸在偶联剂及催化剂的作用下进行酯化反应得到式(1)的10-甲氧基喜树碱衍生物。
其中,所述的10-甲氧基喜树碱衍生物的制备方法,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);所述的催化剂选自吡啶和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在制备抗肿瘤药物中的应用。
体外活性筛选实验表明具有通式(1)的10-甲氧基喜树碱衍生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2774作为受试细胞株,采用噻唑蓝比色法,测定了10-甲氧基喜树碱衍生物的半数抑制浓度(IC50),其中10-甲氧基喜树碱-20-O-(N’-叔丁氧羰基)-甘氨酸酯IC50为355.91±43.38纳摩/毫升,10-甲氧基喜树碱-20-O-(N’-叔丁氧羰基)-L-丙氨酸酯IC50为46.73±21.74纳摩/毫升,10-甲氧基喜树碱-20-O-(N’-叔丁氧羰基)-L-苯丙氨酸酯IC50为393.56±21.74纳摩/毫升,10-甲氧基喜树碱-20-O-(N’-叔丁氧羰基)-L-缬氨酸酯IC50为1971.30±93.59纳摩/毫升,10-甲氧基喜树碱-20-O-丙酸酯IC50为841.53±50.11纳摩/毫升。
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:
具有通式(1)的喜树碱衍生物,式中,R选自氢、C1-6烷基、卤代C1-6烷基、芳基取代C1-6烷基、磷酸基取代C1-6烷基、氨基取代C1-6烷基、羧基取代C1-6烷基、羟基取代C1-6烷基、酰胺基取代C1-6烷基,R1选自氢、叔丁氧羰基取代氨基。
所述的喜树碱衍生物,当R1选自氢时,R选自:
-CH3
所述的喜树碱衍生物,当R1选自叔丁氧羰基取代氨基时,R是:
-H-CH3
所述的喜树碱衍生物,当R1选自叔丁氧羰基取代氨基时,R是:
-CH3
制备所述的喜树碱衍生物的方法,10-甲氧基喜树碱与N-叔丁氧羰基氨基酸和羧酸在偶联剂及催化剂的作用下进行酯化反应得到式(1)的10-甲氧基喜树碱衍生物。
一种药物组合物,含有所述的喜树碱衍生物,以及药效学上可接受的载体。
所述的药物组合物,可以是片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药***。
所述的化合物在制备抗肿瘤药物中的应用。
实施例1 10-甲氧基喜树碱-20-O-丙酸酯的制备
将0.5毫升丙酸加入到20毫升二甲基亚砜中,搅拌条件下加入0.2克10-甲氧基喜树碱,0.4克DCC和0.06克DMAP,室温下反应24小时,过滤,滤液用100毫升蒸馏水稀释,析出白色沉淀,将沉淀过滤、水洗、烘干,柱色谱分离,得到165毫克淡黄色固体(产率82%)。
1HNMR(400MHz,DMSO-d6,ppm):δ0.92(3H,t,H-19),1.05(3H,t,CH3),2.00(2H,m,H-19),2.53(1H,t,CH2),3.94(3H,s,OCH3),5.25(2H,s,H-5),5.48(2H,s,H-17),7.13(1H,s,H-14),7.48(1H,d,H-11),7.51(1H,s,H-9),8.05(1H,d,H-12),8.53(1H,s,H-7)。
ESIMS m/z:433.3(M+H)+。
实施例2 10-甲氧基喜树碱-20-O-(N’-叔丁氧羰基)甘氨酸酯的制备
将0.52克(N’-叔丁氧羰基)甘氨酸溶于20毫升二甲基亚砜中,搅拌条件下加入0.2克10-甲氧基喜树碱,0.4克CDI和0.06克DMAP,室温下反应24小时,过滤,滤液用100毫升蒸馏水稀释,析出白色沉淀,将沉淀过滤、水洗、烘干,柱色谱分离,得到156毫克淡黄色固体(产率78%)。
1HNMR(400MHz,DMSO-d6,ppm):δ0.94(3H,t,H-18),1.32(9H,s,t-boc),2.13(2H,m,H-19),3.81(1H,dd,C-H),3.90(3H,s,OCH3),3.98(1H,dd,C-H),5.17(2H,s,H-5),5.48(2H,s,H-17),7.13(1H,s,H-14),7.43(1H,d,H-11),7.44(1H,t,N-H),7.47(1H,d,H-9),7.97(1H,d,H-12),8.44(1H,s,H-7)。
ESIMS:m/z 533.3(M+H)+。
实施例3 10-甲氧基喜树碱-20-O-(N’-叔丁氧羰基)-L-丙氨酸酯的制备
将0.56克(N’-叔丁氧羰基)-L-丙氨酸溶于20毫升N,N-二甲基甲酰胺中,搅拌条件下加入0.2克1 0-甲氧基喜树碱,0.5克DCC和0.5毫升吡啶,室温下反应24小时,过滤,滤液用1 00毫升蒸馏水稀释,析出白色沉淀,将沉淀过滤、水洗、烘干,柱色谱分离,得到147毫克淡黄色固体(产率73%)。
1HNMR(400MHz,DMSO-d6,ppm)δ0.96(3H,t,H-18),1.33(3H,t,CH3),1.44(9H,s,t-boc),2.09(2H,m,H-19),3.90(3H,s,OCH3),4.09(1H,t,C-H),5.17(2H,q,H-5),5.48(2H,s,H-17),7.18(1H,s,H-14),7.39(1H,d,H-11),7.46(1H,d,,N-H),7.61(1H,d,H-9),7.90(1H,d,H-12),8.42(1H,s,H-7)。
ESIMS:m/z 548.4(M+H)+。
实施例4 10-甲氧基喜树碱-20-O-(N’-叔丁氧羰基)-L-苯丙氨酸酯的制备
将0.79克(N’-叔丁氧羰基)-L-苯丙氨酸溶于20毫升N,N-二甲基甲酰胺中,搅拌条件下加入0.2克10-甲氧基喜树碱,0.45克EDC.HCl和0.5毫升吡啶,室温下反应24小时,过滤,滤液用100毫升蒸馏水稀释,析出白色沉淀,将沉淀过滤、水洗、烘干,柱色谱分离,得到1 50毫克淡黄色固体(产率75%)。
1HNMR(400MHz,DMSO-d6,ppm):δ0.95(3H,t,H-18),1.47(9H,s,t-boc),2.14(2H,m,H-19),2.98(1H,m,C-H),3.09(1H,m,C-H),3.92(3H,s,OCH3),5.22(2H,s,H-5),5.50(2H,s,H-17),7.16(1H,s,H-14),7.27(5H,m,C5H5),7.47(2H,m,H-11,N-H),7.87(1H,d,H-9),8.16(1H,d,H-12),8.63(1H,s,H-7)。
ESIMS:m/z 624.4(M+H)+。
实施例5 10-甲氧基喜树碱-20-O-(N’-叔丁氧羰基)-L-缬氨酸酯的制备
将0.59克(N’-叔丁氧羰基)-L-缬氨酸溶于20毫升N,N-二甲基甲酰胺中,搅拌条件下加入0.2克10-甲氧基喜树碱,0.45克EDC.HCl和0.06克DMAP,室温下反应24小时,过滤,滤液用1 00毫升蒸馏水稀释,析出白色沉淀,将沉淀过滤、水洗、烘干,柱色谱分离,得到1 44毫克淡黄色固体(产率72%)。
1HNMR(400MHz,DMSO-d6,ppm)δ0.97(9H,t,J=7.2Hz,CH3),1.56(9H,s,t-boc),2.15(3H,m,H-19,C-H),3.98(4H,s,OCH3,C-H),5.22(2H,s,H-5),5.48(2H,s,H-17),7.19(1H,s,H-14),7.47(3H,m,H-11,H-9,N-H),7.93(1H,d,H-12),8.42(1H,s,H-7)。
ESIMS:m/z 576.4(M+H)+。
Claims (6)
1.具有通式(1)的10-甲氧基喜树碱衍生物,其特征在于:
式中,当R1选自叔丁氧羰基取代氨基时,R选自:
和中的一种。
2.按照权利要求1所述的10-甲氧基喜树碱衍生物,其特征在于:当R1选自叔丁氧羰基取代氨基时,R是:
-CH3。
3.一种制备权利要求1所述的10-甲氧基喜树碱衍生物的方法,其特征在于:10-甲氧基喜树碱与(N’-叔丁氧羰基)甘氨酸或(N’-叔丁氧羰基)-L-丙氨酸或(N’-叔丁氧羰基)-L-苯丙氨酸或(N’-叔丁氧羰基)-L-缬氨酸在偶联剂及催化剂的作用下进行酯化反应得到权利要求1所述的喜树碱衍生物;
其中所述的偶联剂选自N,N-二环己基碳二亚胺、N,N-羰基二咪唑或1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,所述的催化剂选自吡啶和4-二甲氨基吡啶。
4.一种药物组合物,其特征在于:含有权利要求1或2所述的任一10-甲氧基喜树碱衍生物,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:所述的药物组合物的剂型是片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或微粒给药***。
6.权利要求1或2所述的10-甲氧基喜树碱衍生物在制备抗肿瘤药物中的应用。
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