CN101139358B - 乙氧基康普立停及其前药的制备和用途 - Google Patents
乙氧基康普立停及其前药的制备和用途 Download PDFInfo
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- CN101139358B CN101139358B CN2006100309097A CN200610030909A CN101139358B CN 101139358 B CN101139358 B CN 101139358B CN 2006100309097 A CN2006100309097 A CN 2006100309097A CN 200610030909 A CN200610030909 A CN 200610030909A CN 101139358 B CN101139358 B CN 101139358B
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- Prior art keywords
- combretastatin
- amino
- ethoxy
- compound
- amino acid
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- -1 Ethoxy combretastatin Chemical compound 0.000 title claims abstract description 84
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims description 33
- 239000000651 prodrug Substances 0.000 title description 11
- 229940002612 prodrug Drugs 0.000 title description 11
- 150000001413 amino acids Chemical class 0.000 claims abstract description 18
- 229950004354 phosphorylcholine Drugs 0.000 claims abstract description 17
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 14
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims abstract description 7
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract 4
- 238000006243 chemical reaction Methods 0.000 claims description 41
- 150000001875 compounds Chemical class 0.000 claims description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
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- OBTIDFCSHQLONE-UHFFFAOYSA-N diphenylphosphane;lithium Chemical compound [Li].C=1C=CC=CC=1PC1=CC=CC=C1 OBTIDFCSHQLONE-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
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- RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 claims description 5
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- AVWCEUGYVSFFHK-UHFFFAOYSA-N diphenyl-[2-[(3,4,5-trimethoxyphenyl)methyl]phenyl]phosphane Chemical compound COC=1C=C(CC2=C(C=CC=C2)P(C2=CC=CC=C2)C2=CC=CC=C2)C=C(C=1OC)OC AVWCEUGYVSFFHK-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本发明公开了一种新的乙氧基康普立停(Combretastatin)及其前药的全合成。在康普立停B芳环的4′位，用乙氧基进行化学修饰，同时把其3′位的羟基改造成磷酸盐或磷酸胆碱内式盐的水溶性前药。同样，对3′位氨基康普立停进行4′位乙氧基化学修饰。进一步在氨基上引入氨基酸侧链，形成氨基酸酰胺水溶性前药。结构如结构式(1)所示。乙氧基康普立停具有较强的抑制微管蛋白集聚能力，可用于抗肿瘤和抗新生血管治疗。
Description
技术领域
本发明涉及药物合成领域，尤其涉及抗癌药物的合成。
背景技术
使君子科(Combretastaceae)植物是一类分布于热带和亚热带的灌木和树木，具有十分重要的医学应用价值。已知的风车藤(Combretum)属植物中有25种在非洲和印度被用于治疗麻风和癌症等。但其中仅有几个种类得到过一些研究，主要是Combretum micrantbum和Combretum zeyberi。Combretum caffrum植物是Combretum属中的一个种，在南非被Zulu人称为Mdulu，在其他地方被称为Bushveld willow，Bushwillow和Rooiblaar。二十世纪70年代末，美国国家癌症研究所在广筛中发现这种植物对小鼠P388淋巴白血病细胞具有很高的抑制作用。80年代开始，对这种植物的研究引起了广泛的兴趣。这一时期，美国亚利桑纳大学癌症研究所所长，化学家佩提特(G.Robert Pettit)和四位同事就从学名为“Combretum caffrum”的南非树种中提取Combretastatins，这种树以前“曾被祖鲁人当成退敌的咒符”，佩提特在《加拿大化学期刊》如此写道，树根的外皮确实具有抗癌效果。以后不仅有大量的高活性的化合物被分离、鉴定出来，而且对其药理作用机制和结构修饰工作也在不断深入(Pettit，G.R.；et al.1)Can.J.Chem.1987，65，2390-2396.2)J.Nat.Prod.1987，50，119-131.3)Experieutia 1989，45，209-211)。Combretastatins的系列化合物具有顺式1，2-二苯乙烯结构。其中combretastatin A-4[CA-4，康普立停，顺式-1-(3，4，5-三甲氧基)苯基-2-(3′-羟基-4′-甲氧基)苯基乙烯]，结构式见通式XVII，具有最强的抑制微管聚合作用(Pettit G R，et al.J.Med.Chem(1995)38 1666-1672)。
最近，由于CA-4作为肿瘤血管靶向试剂，显示出其阻断肿瘤血管的优良特性(Thorpe PE.Clin Cancer Res.2004Jan 15，10(2)：415-27；West CM，Price P.Anticancer Drugs.2004 Mar，15(3)：179-87；Young SL，ChaplinDJ.Expert Opin Investig Drugs.2004 Sep，13(9)：1171-82.)。美国Oxigene，Inc.公司用CA-4作为抗肿瘤新药，已进入III期临床研究。1997年日本味之素株式会社(Ajinomoto Co.)T.Hatanaka等人发现把CA-4的3′位的羟基改造成氨基，并把它修饰成氨基酸酰胺水溶性前药后，其抗癌活性大大提高，而其毒性却比CA-4降低了许多(USP5674906)。目前法国Aventis Pharma公司开发3′氨基CA-4氨基酸酰胺(AVE8062)已进入II期临床。
本领域迫切需要寻找Combretastatins类化合物的新的衍生物，其生物活性能有进一步的提高。
发明内容
本发明旨在提供一种乙氧基康普立停衍生物，其结构如通式I。
本发明的另一个目的是提供通式I化合物的制备方法。
本发明的第三个目的是提供含有通式I化合物的药物组合物。
本发明的第四个目的是提供通式I化合物的医药用途。
在本发明的第一方面，提供了一种由通式I表示的化合物：
其中：
R为羟基、氨基、硝基、卤素、烷氧基、磷酸、磷酸胆碱、氨基酸侧链或其药学上可接受的盐。
在另一优选例中，所述的R为羟基、氨基、磷酸、磷酸胆碱、氨基酸侧链或其药学上可接受的盐。
在另一优选例中，所述的R为羟基、氨基、磷酸二钠盐、磷酸铵盐、磷酸胆碱内式盐、或是-NH(COCHR′NH)m-H，其中R′是氢、天然氨基酸侧链、苯基，m表示1-3的整数。
在另一优选例中，所述的R为-OH、-NH2、-OPO2Na2、-OPO3CH2CH2NMe3、-NHCOCH2NH2、或-NHCOCHNH2CH2OH。
在本发明的第二方面，提供了一种通式I化合物的制备方法，它包括步骤：
(1)对羟基间甲氧基苯甲醛II，在相转移催化下，用溴乙烷进行乙基化反应，形成4-乙氧基-3-甲氧基苯甲醛III；
(2)用二苯基膦锂，选择性脱去间位甲基，转化成羟基，得到4-乙氧基-3-羟基苯甲醛IV；
(3)将4-乙氧基-3-羟基苯甲醛IV进行羟基保护，然后与3，4，5-三甲氧基苄基三苯膦叶立德发生维悌希反应，脱保护后，得到乙氧基康普立停VI；
(4)乙氧基康普立停VI在磷酰化试剂的作用下，形成乙氧基康普立停磷酸酯衍生物；
(5)乙氧基康普立停磷酸酯衍生物在碱性条件下形成乙氧基康普立停磷酸盐或乙氧基康普立停磷酸胆碱内式盐。
在另一优选例中，步骤(4)中所述的磷酰化试剂选自：亚磷酸二苄酯或2-氯-1，3，2-二氧膦杂环戊烷。
在另一优选例中，步骤(3)中用三苯甲基氯，实施间位羟基保护反应。
在另一优选例中，步骤(3)中(Z)-1-(3，4，5-三甲氧基苯基)-2-(3′-三苯甲氧基-4′-乙氧基苯基)乙烯在浓盐酸和三氟乙酸作用下，脱去三苯甲基，生成乙氧基康普立停VI。
在另一优选例中，步骤(5)中磷酸酯衍生物通过裂解反应，在碱性条件下，转换成乙氧基康普立停磷酸盐前药，更优选pH＝8-10。
在另一优选例中，步骤(5)中磷酸酯衍生物在叔胺的作用下，形成乙氧基康普立停磷酸胆碱内式盐前药。
在另一优选例中，通式I化合物的制备方法包括步骤：
(a)对羟基间硝基苯甲醛IX，在相转移催化下，用溴乙烷进行乙基化反应，形成4-乙氧基-3-硝基苯甲醛X；
(b)在254nm的紫外光催化下，4-乙氧基-3-硝基苯甲醛X与3，4，5-三甲氧基苄基三苯膦叶立德发生维悌希反应，生成(Z)-1-(3，4，5-三甲氧基苯基)-2-(3′-硝基-4′-乙氧基苯基)乙烯XI；
(c)(Z)-1-(3，4，5-三甲氧基苯基)-2-(3′-硝基-4′-乙氧基苯基)乙烯XI经还原剂还原硝基成氨基，生成3′位氨基乙氧基康普立停XII；
(d)将3′位氨基乙氧基康普立停XII与氨基酸衍生物反应，形成其氨基酸酰胺衍生物；
(e)在碱性条件下，上述氨基酸酰胺衍生物生成3′-氨基乙氧基康普立停氨基酸酰胺。
在另一优选例中，步骤(c)中所述的还原剂选自：氯化亚锡、锌粉/乙酸、硫代硫酸钠或二氯化镍/硼氢化钠。
在另一优选例中，步骤(d)中，在二环己基碳二亚胺(DCC)和1-羟基苯并三唑(HOBt)或六氟合磷氢酸苯并三唑-1-基-氧-三(二甲氨基)鏻(BOP试剂)催化下，(Z)-1-(3，4，5-三甲氧基苯基)-2-(3′-氨基-4′-乙氧基苯基)乙烯与N-α-9-芴基甲氧羰基氨基酸衍生物(FmocAA)反应，转换3′位氨基成Fmoc-氨基酸酰胺。
在另一优选例中，步骤(e)中(Z)-1-(3，4，5-三甲氧基苯基)-2-(3′-氨基-4′-乙氧基苯基)乙烯-Fmoc-氨基酸酰胺脱去Fmoc，生成3′-氨基乙氧基康普立停氨基酸酰胺水溶性前药。所述的碱性条件优选为氢氧化钠水溶液。
在本发明的第三方面，提供了一种药物组合物，它含有治疗有效量的通式I的化合物和药学上可接受的载体。
在另一优选例中，所述的药物组合物选自以下剂型：冻干粉剂、粉剂、粒剂、片剂、胶囊、糖浆、栓剂、注射剂、乳剂、酊剂、悬浮液、溶液的形式静脉注射或口服给药。
在本发明的第四方面，提供了一种通式I化合物在制备微管蛋白聚集抑制剂中的应用。
在本发明的第五方面，提供了一种通式I化合物在制备治疗非正常新生血管引起的疾病的药物中的应用。
在另一优选例中，通式I所述的化合物可用于治疗非正常新生血管引起的各种肿瘤的生长和转移，肿瘤主要包括有：肺癌、非小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、前列腺癌、睾丸癌、结肠癌、卵巢癌、膀胱癌、子宫颈癌、黑色素瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊性腺癌、囊性癌、髓状癌、支气管癌、骨细胞癌、上皮癌、胆管癌、绒毛膜癌、胚癌、精原细胞癌、维尔姆斯癌、胶质细胞癌、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血细胞瘤、声带神经瘤、脑膜瘤、成神经细胞瘤、成视神经细胞瘤、成视网膜细胞瘤、神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、纤维腺瘤、纤维软骨瘤、纤维囊瘤、纤维粘液瘤、纤维骨瘤、纤维粘液肉瘤、纤维乳头状瘤、粘液肉瘤、粘液囊瘤、粘液软骨瘤、粘液软骨肉瘤、粘液软骨纤维肉瘤、粘液腺瘤、成粘液细胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂细胞瘤、脂肪软骨瘤、脂肪纤维瘤、脂肪血管瘤、粘液脂瘤、软骨肉瘤、软骨瘤、软骨肌瘤、脊索瘤、绒毛膜腺瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、骨软骨瘤、骨囊瘤、骨牙质瘤、骨纤维瘤、骨纤维肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管软骨瘤、成血管细胞瘤、血管角质瘤、血管神经胶质瘤、血管内皮瘤、血管纤维瘤、血管肌瘤、血管脂肪瘤、血管淋巴管瘤、血管脂肪平滑肌瘤、血管肌脂瘤、血管肌神经瘤、血管粘液瘤、血管网状内皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、淋巴管纤维瘤、淋巴细胞瘤、淋巴上皮瘤、成淋巴细胞瘤、内皮瘤、成内皮细胞瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纤维瘤、横纹肌瘤、横纹肌肉瘤、横纹肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病细胞、红细胞增多症、淋巴瘤、多发性骨髓瘤。
在另一优选例中，通式I所述的化合物可用于治疗非正常新生血管引起的各种有关疾病，主要有：风湿性关节炎、糖尿病视网膜病、早熟视网膜病、视网膜静脉闭塞、牛皮癣、红斑痤疮、卡波济肉瘤、特异性反应性角膜炎、流行性角膜结膜炎、新生血管性青光眼、细菌性溃疡、真菌性溃疡、单纯性疱疹感染、带状疱疹感染、原生动物感染、分支杆菌感染、多动脉炎、肉样瘤、巩膜炎、潮红、口干眼燥关节炎综合症、全身性红斑狼疮、艾滋病综合症、梅毒。
据此，本发明提供了一种Combretastatins类化合物的新的衍生物，其生物活性有了很大的提高。
附图说明
图1：乙氧基康普立停及其水溶性前药的合成路线。
图2：3′-氨基乙氧基康普立停及其氨基酸酰胺衍生物的合成路线。
其中：
PTC表示相转移催化剂(phase-transfer catalyst)，Cat.表示催化剂，Wittig reaction表示Wittig反应；Ph2PLi表示二苯基膦锂，n-BuLi表示正丁基锂，TFA表示三氟乙酸，iPr2EtN表示二异丙基乙胺，(PhCH2O)2P(O)H表示亚磷酸二苄酯，TMBS表示三甲基溴硅烷，Fmoc-L-Ser表示N-α-9-芴基甲氧羰基-L-丝氨酸衍生物，Fmoc-Gly表示N-α-9-芴基甲氧羰基甘氨酸衍生物，BOP表示六氟合磷氢酸苯并三唑-1-基-氧-三(二甲氨基)鏻，DCC表示环己基碳二亚胺，HOBt表示1-羟基苯并三唑，DMF表示二甲基甲酰胺；NMe3表示三甲胺，aq.NaOH表示稀氢氧化钠，conc.HCl表示浓盐酸。
具体实施方式
发明人经过广泛而深入的研究，意外地发现天然产物(Combretastatin)的B芳环4′位烷氧基是个活性作用点，把康普立停B芳环4′位原有的甲基改造成乙基，可提高其对肿瘤血管靶向活性。
上述化合物的合成是运用了二苯基膦锂选择性脱甲基化关键反应，成功地在B芳环的4′位引入乙氧基。
同时，在上述化合物的合成中，应用了254nm紫外光催化的Wittig反应，提高了反应的立体选择性，使得Z式构型的产物的产率提高了许多。
这些新化合物具有较强的抑制微管蛋白集聚能力，可用于抗肿瘤和抗非正常新生血管治疗。
化合物
本发明提供的乙氧基康普立停(Combretastatin)衍生物是在Combretastatin B芳环4′位引入了乙氧基，在其3′位主要是羟基及其衍生出的磷酸盐或磷酸胆碱内式盐和氨基及其衍生出的氨基酸酰胺水溶性前药。结构如通式I：
其中
R为羟基、氨基、硝基、卤素、烷氧基、磷酸盐、磷酸胆碱内式盐、氨基酸侧链和药学上可接受的盐。
当R选择磷酸盐、磷酸胆碱内式盐、氨基酸侧链和药学上可接受的盐时，形成其水溶性前药。
当R是羟基时，衍生出磷酸盐或是磷酸胆碱内式盐的水溶性前药。
当R是氨基时，衍生出氨基酸酰胺NH(COCHR′NH)n-H的水溶性前药，其中R′是天然氨基酸侧链。
更佳地，R为羟基，优选乙氧基康普立停。R为氨基，优选3′-氨基乙氧基康普立停。结构如通式I，其中的R＝-OH、-NH2、-OP(O)(ONa)2、-OP(O)(O-)(OCH2CH2NMe3)、-NH(COCHR′NH)m-H(R′是氢、天然氨基酸侧链、苯基，m表示1-3的整数)。
本发明提供的乙氧基康普立停衍生物可以与无机碱或有机碱形成药学上可接受的碱加成盐，所述无机碱如氢氧化钾和氢氧化铵，有机碱如脂肪族胺(如三乙胺)、醇胺类(如乙醇胺)、氨基酸(如组氨酸)、氨基糖苷(如新霉胺)。
本发明提供的乙基康普立停衍生物可以与无机酸或有机酸形成药学上可接受的酸加成盐，所述无机酸如盐酸、硫酸和磷酸，有机酸如草酸，富马酸、马来酸、苹果酸，柠檬酸、酒石酸和谷氨酸。
化合物的制备
本发明在相转移催化下，进行乙基化反应；再用二苯基膦锂进行选择性脱甲基反应，从而制备了一系列新型的对乙氧基苯甲醛衍生物。然后以这些新的对乙氧基苯甲醛衍生物为原料实施高立体选择性Wittig反应，获得一系列乙氧基康普立停(Combretastatin)衍生物。然后经磷酸盐化或氨基酸化等的合成工艺优化，制备了一系列乙氧基康普立停(Combretastatin)衍生物的水溶性前药。
(一)制备对乙氧基苯甲醛衍生物
4-羟基-3-甲氧基苯甲醛(香兰素)II或4-羟基-3-硝基苯甲醛IX，用溴乙烷，在无机碱和相转移催化剂的作用下，制备4-乙氧基-3-甲氧基苯甲醛III或4-乙氧基-3-硝基苯甲醛X。
所述的无机碱选自：氢氧化物、碳酸盐中的一种或多种，优选氢氧化钾或/和碳酸钾；所述的相转移催化剂(phase-transfer catalyst，PTC)选自：季铵盐、季磷盐、冠醚、聚乙二醇(PEG)，优选苄基三乙基氯化铵、四丁基硫酸氢铵(TBAB)、18-冠-6、二苯基18-冠-6、二环己基18-冠-6冠醚或PEG-400。
用二醇类化合物，对4-乙氧基-3-甲氧基苯甲醛III进行醛基保护，然后以二苯基膦锂作为3位甲氧基的选择性脱甲基试剂，把甲氧基转化成羟基，得到4-乙氧基-3-羟基苯甲醛IV。
(二)制备乙氧基康普立停(Combretastatin)
在有机碱的催化下，4-乙氧基-3-羟基苯甲醛IV和三苯甲基氯反应，得到3位羟基保护的对乙氧基苯甲醛衍生物V。溴化3，4，5-三甲氧基苄基三苯鏻在正丁基锂的作用下，转变成相应的膦叶立德，和上述3位羟基保护的乙氧基苯甲醛衍生物进行Wittig反应，高产率地生成顺式二苯乙烯衍生物，在浓盐酸和三氟乙酸的联合作用下，脱去三苯甲基，得到乙氧基康普立停VI。
所述的有机碱选自：三乙胺、二异丙基乙胺。
(三)制备3′-氨基乙氧基康普立停
在254nm的紫外光催化下，4-乙氧基-3-硝基苯甲醛X与上述膦叶立德发生Wittig反应，高选择性地生成顺式3′-硝基乙氧基康普立停XI。然后，3’位硝基，用还原剂还原成氨基，还原剂优选氯化亚锡、锌粉/乙酸、硫代硫酸钠、二氯化镍/硼氢化钠。得到3′-氨基乙氧基康普立停XII。
(四)制备乙氧基康普立停的磷酸盐
如图1所示，上述乙氧基康普立停VI的3’位羟基，经过四氯化碳、二异丙基乙胺、亚磷酸二苄酯、三甲基溴硅烷、甲醇钠的作用转化成磷酸二钠盐，生成乙氧基康普立停的磷酸盐VII。
(五)制备乙氧基康普立停的磷酸胆碱内式盐
或者，仍如图1所示，用磷酰化试剂：2-氯-1，3，2-二氧氧化膦杂环戊烷与上述乙氧基康普立停VI的3’位羟基，进行反应，得到乙氧基康普立停环状磷酸酯衍生物。在三甲胺的作用下，其环状磷酸酯衍生物开环，生成乙氧基康普立停的磷酸胆碱内式盐VIII。
(六)制备3′-氨基乙氧基康普立停氨基酸酰胺
如图2所示，上述3′-氨基乙氧基康普立停XII，在N-α-9-芴基甲氧羰基氨基酸衍生物(FmocAA)和BOP试剂或环己基碳二亚胺(DCC)和1-羟基苯并三唑(HOBt)的作用下，在3′-位氨基上引入氨基酸侧链，如结构XIII和XIV。然后在氢氧化钠的作用下，脱去Fmoc保护转换成氨基酸酰胺，得一系列3′-氨基乙氧基康普立停氨基酸酰胺衍生物，如结构XV和XVI。
药物组合物
将治疗有效量的通式I化合物和药学上可接受的载体混合，制备成组合物的形式；其中治疗有效量的通式I化合物占组合物0.1-99％(w/w)。本发明的组合物可以多种剂型存在。所述的剂型可以是冻干粉剂、粒剂、粉剂、片剂、胶囊、糖浆、栓剂、注射剂、乳剂、酊剂、悬浮液、溶液的形式静脉注射或口服给药剂型。
对于静脉注射给药，可使用冻干粉剂，用生理盐水或葡萄糖溶液配成溶液，进行静脉输液。
对于口服给药，可使用片剂、锭剂、胶囊、丸剂、粉末、颗粒、糊剂、混悬剂、乳剂或者溶液剂。
所用的活性成分的有效剂量可随给药的模式和待治疗的疾病的严重程度而变化。然而，通常当本发明的化合物每天以约0.5-500mg/kg动物体重的剂量给予时，能得到令人满意的效果，较佳地每天以2-4次分开的剂量给予，或以缓释形式给药。对大部分大型哺乳动物而言，每天的总剂量约为1-100mg。适用于内服的剂量形式，包含与固态或液态药学上可接受的载体混合的约0.5-500mg的活性化合物。可调节此剂量方案以提供最佳治疗应答。例如，由治疗状况的迫切要求，可每天给予若干次分开的剂量，或将剂量按比例地减少。通常，成年人的口服每日的合适临床剂量的选择范围为1-1000mg，优选为10-200mg，成人非口服的每日剂量为0.1-100mg，优选1-100mg。
按上述方法制备得到的本发明乙氧基康普立停(Combretastatin)衍生物，用作血管靶向药物时，该药剂可通过静脉注射或口服给药。药剂剂量因疾病的发展程度而异，成人通常在1和3000mg之间。
在优选例中，本发明的化合物可通过口服以及静脉内途径给药。固态载体包括：淀粉、乳糖、磷酸氢钙、微晶纤维素、蔗糖和白陶土，而液态载体包括：无菌水、聚乙二醇、甘露醇、非离子型表面活性剂和食用油(如玉米油、花生油和芝麻油)，只要适合活性成分的特性和所需的特定给药方式。在制备药物组合物中通常使用的佐剂也可有利地被包括，例如调味剂、色素、防腐剂和抗氧化剂如维生素E、维生素C、BHT和BHA。
如本文所用，静脉注射包括腹膜内注射和滴注输液，使用冻干粉剂，用生理盐水或葡萄糖溶液配成的溶液。其中冻干粉剂由本领域常规方法制得。
本发明乙氧基康普立停衍生物配制成口服制剂，包括片剂、胶囊。这种剂型可用有效组分与至少一种添加剂混合而成，这些添加剂包括赋形剂、粘合剂、崩解剂、润滑剂、着色剂、矫味剂等，并将所形成的混合物制成粉剂、粒剂、片剂、涂层片剂、丸剂、胶囊等剂型。赋形剂包括乳糖、玉米淀粉、糖类，葡萄糖，山梨醇，结晶纤维素中的一种或多种。粘合剂包括聚乙烯醇、甲基纤维素、乙基纤维素、阿拉伯树胶、黄耆胶、明胶、紫胶、羟丙基纤维素、羟丙基淀粉，聚乙烯吡咯烷酮中的一种或多种。崩解剂包括淀粉、琼脂、凝胶粉，结晶纤维素、碳酸钙、碳酸氢钠、柠檬酸钙、环糊精，果胶中的一种或多种。润滑剂包括硬脂酸镁、滑石、聚乙二醇、硅石，硬化植物油中的一种或多种。着色剂包括允许加到药品中的色素。矫味剂包括可可粉、薄荷醇、薄荷油、精制冰片，以及肉桂。如果需要，这些片剂和粒剂可用蔗糖、明胶等包衣。一般这些剂型可含有另外的添加剂，包括惰性稀释剂，防腐剂如对羟苯甲酸酯类，山梨酸，抗氧剂如维生素C、α-维生素E和半胱氨酸，分解剂，粘结剂，增稠剂，缓冲液，甜味剂，调味剂和香料。片剂和丸剂也可覆以肠衣。口服的液体剂型包括可药用的乳剂、糖浆、酊剂、悬液和溶液，可以含有常用的惰性稀释剂，如水。
本发明的主要优点在于：
在天然产物Combretastatin(康普立停)的B芳环的4′位引入乙氧基，提高了其对肿瘤血管的靶向活性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分比和份数按重量计。
实施例1
制备4-乙氧基-3-甲氧基苯甲醛：
在装有温度计、机械搅拌、回流冷凝管、1000ml四颈烧瓶加入4-羟基-3-甲氧基苯甲醛62克(0.41mol)、400mL异丙醇，搅拌20分钟，用恒压滴液漏斗缓缓滴入5克18-冠-6醚和106.3克氢氧化钠(2.66mol.)的120毫升水溶液，搅拌30分钟，将反应体系加热到60℃，在此温度下，滴入溴乙烷67.3克(0.62mol.)5-6小时，TLC跟踪。反应完成后将体系冷却下来(15℃)加入400mL的水中止反应，产物用乙醚(3×300mL)萃取，有机相用水洗至中性，无水MgSO4干燥。蒸去部分乙醚，加入大量石油醚，沉淀出粗产品。用乙醚/石油醚重结晶得到4-乙氧基-3-甲氧基苯甲醛67克，产率91％。1H-NMR(ppm)δ：9.87(1H，s；-CHO)；7.31(1H，m；2-ArH)；7.26(1H，m；6-ArH)；6.86(1H，m；5-ArH)；3.98(2H，q；-CH2)；3.73(3H，s；-OCH3)；1.42(3H，t；-CH3)。MS(m/Z)：180(M+)。
实施例2
制备4-乙氧基-3-硝基苯甲醛：
按实施例一，用4-羟基-3-硝基苯甲醛68.5克(0.41mol.)代替4-羟基-3-甲氧基苯甲醛，得到4-乙氧基-3-硝基苯甲醛68.7克，产率86％。1H-NMR(ppm)δ：9.96(1H，s；-CHO)；7.73(1H，m；2-ArH)；7.58(1H，m；6-ArH)；7.33(1H，m；5-ArH)；4.15(2H，q；-CH2)；3.82(3H，s；-OCH3)；1.53(3H，t；-CH3)。MS(m/Z)：195(M+)
实施例3
制备4-乙氧基-3-羟基苯甲醛：
步骤1，在氩气的保护之下，取4-乙氧基-3-甲氧基苯甲醛54克(0.3mol)加入到三颈瓶中，然后加入乙二醇130克(2.1mol)，原甲酸三乙酯133克(0.9mol)，100℃左右回流，加入1ml三氟化硼乙醚溶液，作为催化剂。反应24小时，TLC跟踪。冷却到室温，加入200ml 15％氢氧化钠水溶液，用300ml的乙醚萃取，用饱和食盐水洗涤，无水硫酸镁干燥，减压蒸去乙二醇和原甲酸三乙酯，得到黄色油状物。
步骤2，在1.28M二苯基膦锂四氢呋喃溶液200ml中，分批加入上述缩醛56克(0.25mol)。室温搅拌3-4小时，TLC跟踪。加水中止反应，加入200ml 30％的氢氧化钠溶液后，用300ml乙醚进行萃取。水层在冷却下，用盐酸酸化，调节pH值3-4左右。然后用500ml乙醚萃取，合并乙醚萃取液，用水和饱和食盐水洗涤，无水硫酸镁干燥，过滤，减压除去溶剂，得到黄色固体。苯/石油醚重结晶，得浅黄色晶体35.3克，产率85％。1H-NMR(ppm)δ：9.90(1H，s；-CHO)；7.32(1H，m；2-ArH)；7.27(1H，m；6-ArH)；6.89(1H，m；5-ArH)；4.88(1H，br；-OH)；4.17(2H，q；-CH2)；1.53(3H，t；-CH3)。13C-NMR(ppm)δ：192.0(CHO)，157.6(4-ArC)，143.3(3-ArC)，129.6(1-ArC)，124.5(6-ArC)，116.7(2-ArC)，116.6(5-ArC)，82.1(-OCH2)，23.5(-CH3)。MS(m/Z)：166(M+)。
实施例4
制备(Z)-1-(3，4，5-三甲氧基苯基)-2-(3’-羟基-4’-乙氧基苯基)-乙烯(乙氧基康普立停)：
步骤1，在氩气氛下，加入4-乙氧基-3-羟基苯甲醛11.0g(0.066mol.)，三苯甲基氯21.1g(0.076mol.)，干燥四氢呋喃42ml到500ml四颈烧瓶中，室温下搅拌均匀。然后缓慢滴加三乙胺1.3ml。滴完后继续搅拌1小时，TLC跟踪，反应完成后，加水50ml中止。搅拌30分钟，加入乙酸乙酯100ml，溶解絮状沉淀。加入正庚烷250ml，沉淀出颗粒状浅黄色粗品。过滤，所得的固体用水洗两次，再用乙酸乙酯/石油醚(10ml/20ml)洗涤，得到浅白色晶体。此晶体用乙酸乙酯/石油醚重结晶，得到白色的大颗粒晶体25克，产率93％。1H-NMR(ppm)δ：9.91(1H，s；-CHO)；7.33(1H，m；2-ArH)；7.26(1H，m；6-ArH)；7.19(m，15H，Tr-H)；6.89(1H，m；5-ArH)；4.17(2H，q；-CH2)；1.53(3H，t；-CH3)。
步骤2，在氩气保护下，将溴化三甲氧基苯基亚甲基三苯鏻15g(28.7mmol.)悬浮于300ml THF中，冷却到-15℃左右。滴入1.6mol/L的正丁基锂环己烷溶液22ml，反应1小时。将11.8克(29mmol.)上述所得醛溶解于24ml THF中，缓慢滴加入反应中。TLC跟踪，搅拌过夜，反应温度升到室温。次日，将溶液温度降到-5℃，加入饱和食盐水中止反应。分出有机层，除去溶剂。经快速柱层析(硅胶柱，4∶1正己烷/乙酸乙酯)分离得到13.7克白色晶体，产率83.5％。1H-NMR(ppm)δ：7.12(m，15H，Tr-H)；6.97(d，1H，2’-H)；6.81(dd，1H，6’-H)；6.75(d，1H，5’-H)；6.59(s，2H，2，6-H)；6.47(d，1H，J＝12Hz，1a-H)；6.41(d，1H，J＝12Hz，1a’-H)；4.13(2H，q；-CH2)；3.88(s，3H，4-OCH3)；3.71(s，6H，3，5-OCH3)；1.55(3H，t；-CH3)。
步骤3，室温下，取上述Wittig反应产物9.6g(16.8mmol.)，用20ml甲苯溶解。然后滴加37％HCl 4ml(内含0.2ml三氟乙酸)，TLC跟踪，反应完成后，加水中止反应。反应体系冷却到0℃-5℃。在搅拌状态下重结晶。过滤出白色晶体5.1克，产率92％。1H-NMR(ppm)δ：7.02(d，1H，2’-H)；6.94(dd，1H，6’-H)；6.80(d，1H，5’-H)；6.62(s，2H，2，6-H)；6.46(d，1H，J＝12Hz，1a-H)；6.40(d，1H，J＝12Hz，1a’-H)；5.51(broad，1H；OH)；4.16(2H，q；-CH2)；3.86(s，3H，4-OCH3)；3.70(s，6H，3，5-OCH3)；1.52(3H，t；-CH3)。MS(m/Z)：330(M+)。高分辨质谱，计算值：330.15，实测值：330.16。
实施例5
制备(Z)-1-(3，4，5-三甲氧基苯基)-2-(3’-氨基-4’-乙氧基苯基)-乙烯(3′-氨基乙氧基康普立停)：
步骤1，在光化学合成器中，氩气保护下，将溴化三甲氧基苯基亚甲基三苯鏻15g(28.7mmol.)悬浮于300ml THF中，冷却到-15℃左右。滴入1.6mol/L的正丁基锂环己烷溶液22ml，反应1小时。然后，开启254nm紫外灯，在UV辐射下，将5.7克(29mmol.)4-乙氧基-3-硝基苯甲醛24ml THF溶液，缓慢滴加入反应中。TLC跟踪，搅拌过夜，反应温度升到室温。次日，关闭紫外灯，将溶液温度降到-5℃，加入饱和食盐水中止反应。分出有机层，除去溶剂。经常压柱层析(硅胶柱，4∶1正己烷/乙酸乙酯)分离得到6.5克浅黄色晶体，产率63％。1H-NMR(ppm)δ：7.32(d，1H，2’-H)；7.16(dd，1H，6’-H)；6.90(d，1H，5’-H)；6.64(s，2H，2，6-H)；6.49(d，1H，J＝12.2Hz，1a-H)；6.43(d，1H，J＝12.2Hz，1a’-H)；4.18(2H，q；-CH2)；3.86(s，3H，4-OCH3)；3.70(s，6H，3，5-OCH3)；1.55(3H，t；-CH3)。MS(m/Z)：359(M+)。高分辨质谱，计算值：359.14，实测值：359.13。
步骤2，搅拌下，取取(Z)-1-(3，4，5-三甲氧基苯基)-2-(3’-硝基-4’-乙氧基苯基)-乙烯4.1克(10.8mmol.)溶解在350ml醋酸，然后加入100克锌粉(＜10μm)。继续搅拌6小时。停止反应后，用布氏漏斗上垫铺约1公分厚的硅藻土，抽滤反应液，滤液在旋转蒸发仪上浓缩。然后快速柱层析(4∶1正己烷/乙酸乙酯)，得到产品，用约9∶1正己烷/乙酸乙酯重结晶。得到无色晶体2.7克，产率77％。1H-NMR(ppm)δ：7.08(d，1H，2’-H)；6.92(dd，1H，6’-H)；6.76(d，1H，5’-H)；6.62(s，2H，2，6-H)；6.49(d，1H，J＝12.2Hz，1a-H)；6.43(d，1H，J＝12.2Hz，1a’-H)；4.73-4.25(broad，2H，NH2)；4.18(2H，q；-CH2)；3.86(s，3H，4-OCH3)；3.70(s，6H，3，5-OCH3)；1.55(3H，t；-CH3)。MS(m/Z)：329(M+)。高分辨质谱，计算值：329.16，实测值：329.18。
实施例6
制备乙氧基康普立停磷酸二钠盐
步骤1：在氩气氛下，1000ml四颈烧瓶中加入41.6克乙氧基康普立停(126mmol)用400mL干燥乙腈溶解，冷却到-25℃，然后加入61ml四氯化碳，继续搅拌5分钟后，加入47ml二异丙基乙基胺和1.5克4-二甲基氨基吡啶(DMAP)，1分钟后，慢慢加入41ml二苄基亚磷酸酯(80％)；保持温度在-10℃以下，继续反应3.5小时，TLC跟踪，当反应完全时，加入100ml 0.5M的KH2PO4，自然升温到室温。乙酸乙酯萃取，合并有机层，用蒸馏水、饱和食盐水依次洗涤，无水硫酸镁干燥，减压蒸去溶剂，得到混浊油状物。经快速柱层析(硅胶，3∶2石油醚/乙酸乙酯)，分离得到75克浅黄色的油状物。经乙酸乙酯-正己烷重结晶得到无色针状晶体68.4克。产率92％。
步骤2，在1000ml四颈烧瓶中，加入干燥的上述得到的磷酸苄酯65克(110mmol.)，用250ml的干燥无水乙腈溶解，在15℃，氩气氛下，搅拌。快速滴加45ml三甲基溴硅烷(TMBS)，5-10分钟以后，加入18克甲醇钠的70ml无水甲醇溶液，反应体系立即变成乳白色的悬浊液。半小时以后，加入36ml无水甲醇，36ml丙酮，搅拌过夜。抽滤，得到白色固体，用无水甲醇和丙酮洗涤，真空干燥。用水/甲醇/丙酮重结晶得到白色粉末43克。产率86％。1H-NMR(ppm)δ：7.11(d，1H，2’-H)；6.98(dd，1H，6’-H)；6.87(d，1H，5’-H)；6.64(s，2H，2，6-H)；6.47(d，1H，J＝12Hz，1a-H)；6.42(d，1H，J＝12Hz，1a’-H)；4.18(2H，q；-OCH2)；3.86(s，3H，4-OCH3)；3.70(s，6H，3，5-OCH3)；1.52(3H，t；-CH3)。MS(m/Z)：454(M+)。高分辨质谱，计算值：454.08，实测值：454.06。
实施例7
制备乙氧基康普立停磷酸胆碱内式盐
步骤1，在干燥的500ml的三颈烧瓶中注入68克(0.5mol)干燥的三氯化磷100ml二氯甲烷溶液。冷却系统，保持0℃，滴加31克(0.5mol)干燥的乙二醇的100ml二氯甲烷溶液。滴加完毕升温到室温，继续反应3个小时。蒸除溶剂，残液减压蒸馏收集60℃/20mmHg的馏份，得到2-氯-1，3，2-二氧氧化环膦杂烷41克，产率65％。1H-NMR(CDCl3，500M)δ：4.46(m，2H，a-CHCH-)，4.24(m，2H，e-CHCH-)。
步骤2，在100ml的三颈烧瓶中加入50ml的无水苯，然后再加入25.3克(0.2mol)的2-氯-1，3，2-二氧环膦杂戊烷，缓缓通氧气至溶液中，保持通氧气约1小时后，加热至回流，在回流状态下反应5-6小时，冷却到室温，蒸除溶剂，得到的残余液体减压蒸馏收集90℃/1mmHg馏份。得到2-氯-1，3，2-二氧氧化环膦杂戊烷12.3克，产率43％。1H-NMR(CDCl3，500M)δ：4.64(m，2H，a-CHCH-)，4.56(m，2H，e-CHCH-)。
步骤3，在氩气氛下，3.3克(10mmol)乙氧基康普立停和1.0克(10mmol)三乙胺溶于20ml干燥的苯。冷却到-40℃，在搅拌的条件下，滴加1.42克(10mmol)2-氯-1，3，2-二氧氧化环膦杂戊烷的苯溶液20ml。滴加完毕，持续反应半小时，然后在室温的条件下继续搅拌10小时。过滤除去三乙胺的盐酸盐，滤液减压蒸去部分溶剂，然后用15％碳酸钠溶液15ml洗涤，加入50ml乙醚萃取，分液后，水层再用50ml乙醚萃取，合并醚层，用10％碳酸钠溶液20mlx2洗涤。干燥，过滤，蒸除乙醚后，得到浅黄色固体磷酯3.5克(产率81％)。在前述磷酯中，加入50ml乙腈，溶解完全后，加入三甲胺水溶液(28％)5ml，室温搅拌20小时，TLC跟踪。反应完成后，加入50ml丙酮，冷却到-30℃，搅拌下结晶。抽滤，干燥得白色粗产品。用95％乙醇重结晶，得白色晶体3克，产率76％。1H-NMR(CDCl3，500M)δ：7.27(d，1H，2’-H)，6.63(dd，1H，6’-H)，6.51(d，1H，5’-H)，6.46(d，1H，1a-H)，6.380(s，2H，2，6-H)，6.20(d，1H，1a’-H)，4.62(m，2H，a-CHCH-)，4.53(m，2H，e-CHCH-)，4.18(2H，q；-OCH2)，3.86(s，3H，4-OCH3)；3.70(s，6H，3，5-OCH3)；3.18(s，9H，NMe3)，1.52(3H，t；-CH3)。MS(m/Z)：495(M+)。高分辨质谱，计算值：495.20，实测值：495.22。
实施例8
制备3′-氨基乙氧基康普立停甘氨酰胺
步骤1，取3′-氨基乙氧基康普立停4.28克(13mmol.)和Fmoc-甘氨酸4.75克(16mmol.)以及BOP试剂22.7克(51.6mmol.)溶于100mlDMF。在搅拌下，将反应混合物加热到60℃，反应2小时，TLC跟踪。反应完成后，冷却，加入饱和碳酸氢钠溶液100ml，混合均匀。用二氯甲烷120mlx3萃取，有机层经无水硫酸镁干燥，减压浓缩。然后，经快速柱层析(硅胶，2∶1正己烷/乙酸乙酯)分离得到白色泡沫状物质3.3克，产率42％。1H-NMR(CDCl3，500M)δ：9.61(brs.1H，-NH)；7.74(m，2H，Fmoc)；7.59(d，2H，J＝6.2Hz，Fmoc)；7.37(m，2H，Fmoc)；7.29(m，2H，Fmoc)；7.08(d，1H，2’-H)；6.92(dd，1H，6’-H)；6.76(d，1H，5’-H)；6.62(s，2H，2，6-H)；6.49(d，1H，J＝12.2Hz，1a-H)；6.43(d，1H，J＝12.2Hz，1a’-H)；5.79(brs.1H，Gly-NH)；4.38(d，2H，J＝7.0Hz，Fmoc)；4.22(t，1H，J＝7.0Hz，Fmoc)；4.18(2H，q；-CH2)；4.04(m，2H，Gly-CH2)；3.86(s，3H，4-OCH3)；3.70(s，6H，3，5-OCH3)；1.55(3H，t；-CH3)。MS(m/Z)：608(M+)。高分辨质谱，计算值：608.25，实测值：608.27。
步骤2，取上述得到的(Z)-1-(3，4，5-三甲氧基苯基)-2-(3’-氨基-4’-乙氧基苯基)-乙烯-Fmoc-甘氨酰胺2.2克(3.6mmol.)溶于40ml甲醇。在搅拌下，加入2ml2N氢氧化钠溶液，室温反应3小时，TLC跟踪。反应完成后，冷却，加入饱和碳酸氢钠溶液20ml，混合均匀。用二氯甲烷50mlx3萃取，有机层经无水硫酸镁干燥，减压浓缩。然后，经常压柱层析(硅胶，9∶1二氯甲烷/甲醇)分离得到无色泡沫状物质0.97克，产率70％。1H-NMR(CDCl3，500M)δ：9.61(brs.1H，-NH)；7.08(d，1H，2’-H)；6.92(dd，1H，6’-H)；6.76(d，1H，5’-H)；6.62(s，2H，2，6-H)；6.49(d，1H，J＝12.2Hz，1a-H)；6.43(d，1H，J＝12.2Hz，1a’-H)；4.81-4.32(broad，2H，Gly-NH2)；4.18(2H，q；-CH2)；4.04(brs，2H，Gly-CH2)；3.86(s，3H，4-OCH3)；3.70(s，6H，3，5-OCH3)；1.55(3H，t；-CH3)。MS(m/Z)：386(M+)。高分辨质谱，计算值：386.18，实测值：386.20。
实施例9
制备3′-氨基乙氧基康普立停丝氨酰胺
步骤1，取3′-氨基乙氧基康普立停4.28克(13mmol.)和Fmoc-丝氨酸5.89克(16mmol.)以及DCC 3.37克(16mmol.)和HOBt 2.44克溶于80mlDMF。在搅拌下，反应混合物室温反应5小时，TLC跟踪。反应完成后，冷却，加入加入乙酸乙酯50ml稀释，混合均匀。过滤，经无水硫酸镁干燥，减压浓缩。然后，经快速柱层析(硅胶，2∶1正己烷/乙酸乙酯)分离得到白色泡沫状物质5.1克，产率61％。1H-NMR(CDCl3，500M)δ：9.73(brs.1H，-NH)；7.73(m，2H，Fmoc)；7.56(d，2H，J＝6.2Hz，Fmoc)；7.35(m，2H，Fmoc)；7.22(m，2H，Fmoc)；7.05(d，1H，2’-H)；6.91(dd，1H，6’-H)；6.74(d，1H，5’-H)；6.60(s，2H，2，6-H)；6.51(d，1H，J＝12.2Hz，1a-H)；6.43(d，1H，J＝12.2Hz，1a’-H)；5.82(brs.1H，Ser-NH)；4.63(brs.1H，Ser-OH)4.38(d，2H，J＝7.0Hz，Fmoc)；4.22(t，1H，J＝7.0Hz，Fmoc)；4.18(2H，q；-CH2)；3.91(m，1H，Ser-CH)；3.85(s，3H，4-OCH3)；3.71(s，6H，3，5-OCH3)；2.66(m，2H，Ser-CH2)1.56(3H，t；-CH3)。MS(m/Z)：638(M+)。高分辨质谱，计算值：638.26，实测值：638.27。
步骤2，取上述得到的(Z)-1-(3，4，5-三甲氧基苯基)-2-(3’-氨基-4’-乙氧基苯基)-乙烯-Fmoc-丝氨酰胺1.9克(3.0mmol.)溶于20ml甲醇和20ml二氯甲烷混合溶剂中。在搅拌下，加入3.4ml 2N氢氧化钠溶液，室温反应24小时，TLC跟踪。反应完成后，冷却，加入饱和氯化钠溶液20ml，混合均匀。用二氯甲烷50mlx3萃取，有机层经无水硫酸镁干燥，减压浓缩。然后，经常压柱层析(硅胶，9∶1二氯甲烷/甲醇)分离得到无色泡沫状物质0.62克，产率50％。1H-NMR(CDCl3，500M)δ：9.75(brs.1H，-NH)；7.08(d，1H，2’-H)；6.94(dd，1H，6’-H)；6.75(d，1H，5’-H)；6.63(s，2H，2，6-H)；6.53(d，1H，J＝12.2Hz，1a-H)；6.45(d，1H，J＝12.2Hz，1a’-H)；5.51-4.72(brs.2H，Ser-NH2)；4.52(brs.1H，Ser-OH)；4.19(2H，q；-CH2)；3.92(m，1H，Ser-CH)；3.86(s，3H，4-OCH3)；3.72(s，6H，3，5-OCH3)；2.68(m，2H，Ser-CH2)1.57(3H，t；-CH3)。MS(m/Z)：416(M+)。高分辨质谱，计算值：416.19，实测值：416.20。
对比例
丙氧基康普立停的制备
按实施例1，用正溴丙烷代替溴乙烷，制得4-丙氧基-3-甲氧基苯甲醛。然后，按实施例3和4制备丙氧基康普立停。1H-NMR(ppm)δ：7.02(d，1H，2’-H)；6.94(dd，1H，6’-H)；6.80(d，1H，5’-H)；6.62(s，2H，2，6-H)；6.46(d，1H，J＝12Hz，1a-H)；6.40(d，1H，J＝12Hz，1a’-H)；5.51(broad，1H；OH)；4.16(q，2H；-CH2)；3.86(s，3H，4-OCH3)；3.70(s，6H，3，5-OCH3)；2.27(m，2H；-CH2)；1.18(3H，t；-CH3)。MS(m/Z)：344(M+)。高分辨质谱，计算值：344.18，实测值：344.16。
实施例10
体外抗肿瘤活性评估
体外培养的肿瘤细胞经乙烷氧基康普立停衍生物处理72小时后，应用MTT或SRB方法评价其对肿瘤增殖的抑制作用，并与CA-4比较。
细胞株：H460：人肺癌细胞，SGC7901：人胃癌细胞，HT-29：人结肠癌细胞，Bel-7402：人肝癌细胞。
实验设计：细胞与不同浓度化合物(分别为100，10，1，0.1，0.01，0.001μM)温育72小时，采用SRB方法评价化合物对细胞增殖的抑制程度，计算抑制率，根据抑制率采用Logit方法计算IC50，比较化合物的体外抗肿瘤活性。
抑制率计算方法：
抑制率(％)＝(对照组OD值-用药OD值)/对照组OD值×100％
结果表明，乙氧基康普立停衍生物的体外抗肿瘤活性比天然化合物Combretastatin A-4的活性在不同种类的癌细胞株中都要大，特别是对结肠癌的抑制活性要比CA-4大50到95倍。而对比例制得的对照物丙氧基康普立停几乎就没有抗肿瘤活性。
实施例11
体外新生血管抑制性能评价
按实施例十的方法，以入脐静脉内皮细胞(HUVEC)为作用对象，考察乙氧基康普立停衍生物的抗新生血管性能。
结果表明，乙氧基康普立停衍生物具有很强的微管蛋白集聚抑制性能，预示着乙氧基康普立停衍生物是一类潜在的肿瘤血管靶向药物。而对比例制得的对照物丙氧基康普立停几乎没有该特性。
实施例12
制备乙氧基康普立停磷酸二钠盐冻干粉剂
| 配方 | 含量(g) |
| 实施例6制得的乙氧基康普立停磷酸二钠盐 | 25 |
| 甘露醇 | 125 |
| 注射用水 | 2500 |
| 制成DD8031DP冻干粉剂 | 0.025/瓶x1000瓶 |
按照处方量精密称取原料，将处方量甘露醇投入，加入约处方总量80％的注射用水搅拌至溶解完全，得到澄清溶液，加入0.1％(g/ml)的针用活性炭，搅拌均匀，静置约10分钟，经0.45μm微孔滤膜过滤，补加注射用水至全量。再经0.22μm微孔滤膜过滤，测定pH值和含量，合格后，定量灌装，冷冻干燥，充氮，压塞，压铝盖，贴签，包装，抽检合格，即得成品。(整个流程均需避光)
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1. 一种由通式I表示的化合物：
其中：
R为羟基、氨基、硝基、卤素、烷氧基、磷酸、磷酸胆碱、氨基酸侧链或其药学上可接受的盐。
2. 如权利要求1所述的化合物，其特征在于，所述的R为羟基、氨基、磷酸、磷酸胆碱、氨基酸侧链或其药学上可接受的盐。
3. 如权利要求1所述的化合物，其特征在于，所述的R为羟基、氨基、磷酸二钠盐、磷酸铵盐、磷酸胆碱内式盐、或是-NH(COCHR′NH)m-H，其中R′是氢、天然氨基酸侧链、苯基，m表示1-3的整数。
4. 如权利要求1所述的化合物，其特征在于，所述的R为-OH、-NH2、-OPO2Na2、-OPO3CH2CH2NMe3、-NHCOCH2NH2、或-NHCOCHNH2CH2OH。
5. 一种如权利要求1所述的化合物的制备方法，其特征在于，它包括步骤：
(1)对羟基间甲氧基苯甲醛II，在相转移催化下，用溴乙烷进行乙基化反应，形成4-乙氧基-3-甲氧基苯甲醛III；
(2)用二苯基膦锂，选择性脱去间位甲基，转化成羟基，得到4-乙氧基-3-羟基苯甲醛IV；
(3)将4-乙氧基-3-羟基苯甲醛IV进行羟基保护，然后与3，4，5-三甲氧基苄基三苯膦叶立德发生维悌希反应，脱保护后，得到乙氧基康普立停VI；
(4)乙氧基康普立停VI在磷酰化试剂的作用下，形成乙氧基康普立停磷酸酯衍生物；
(5)乙氧基康普立停磷酸酯衍生物在碱性条件下形成乙氧基康普立停磷酸盐或乙氧基康普立停磷酸胆碱内式盐。
6. 如权利要求5所述的制备方法，其特征在于，步骤(4)中所述的磷酰化试剂选自：亚磷酸二苄酯或2-氯-1，3，2-二氧膦杂环戊烷。
7. 一种如权利要求1所述的化合物的制备方法，其特征在于，它包括步骤：
(a)对羟基间硝基苯甲醛IX，在相转移催化下，用溴乙烷进行乙基化反应，形成4-乙氧基-3-硝基苯甲醛X；
(b)在254nm的紫外光催化下，4-乙氧基-3-硝基苯甲醛X与3，4，5-三甲氧基苄基三苯膦叶立德发生维悌希反应，生成(Z)-1-(3，4，5-三甲氧基苯基)-2-(3′-硝基-4′-乙氧基苯基)乙烯XI；
(c)(Z)-1-(3，4，5-三甲氧基苯基)-2-(3′-硝基-4′-乙氧基苯基)乙烯XI经还原剂还原硝基成氨基，生成3′位氨基乙氧基康普立停XII；
(d)将3′位氨基乙氧基康普立停XII与氨基酸衍生物反应，形成其氨基酸酰胺衍生物；
(e)在碱性条件下，上述氨基酸酰胺衍生物生成3′-氨基乙氧基康普立停氨基酸酰胺。
8. 一种药物组合物，其特征在于，它含有治疗有效量的如权利要求1所述的化合物和药学上可接受的载体。
9. 一种如权利要求1所述的化合物在制备微管蛋白聚集抑制剂中的应用。
10. 一种如权利要求1所述的化合物在制备治疗非正常新生血管引起的疾病的药物中的应用。
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| US12/439,783 US7838706B2 (en) | 2006-09-07 | 2007-05-16 | Preparation and the use of ethoxy combretastatins and their prodrugs |
| PCT/CN2007/070020 WO2008031333A1 (fr) | 2006-09-07 | 2007-05-16 | Préparation et utilisation d'éthoxy-combretastatines et de leurs promédicaments |
| JP2009527000A JP5250876B2 (ja) | 2006-09-07 | 2007-05-16 | エトキシコンブレタスタチンとそのプロドラッグの製造方法及び用途 |
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| AU2007295835A AU2007295835B2 (en) | 2006-09-07 | 2007-05-16 | The preparation and the use of ethoxy combretastatins and their prodrugs |
| RU2009117488/04A RU2451664C2 (ru) | 2006-09-07 | 2007-05-16 | Способы производства и использования этоксикомбретастатинов и пролекарства на их основе |
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| CN104447598B (zh) * | 2013-09-18 | 2017-09-22 | 浙江大德药业集团有限公司 | Ca‑4的大环多胺衍生物及其抗肿瘤特性 |
| RU2748260C2 (ru) * | 2016-04-04 | 2021-05-21 | Кемосентрикс, Инк. | РАСТВОРИМЫЕ С5аR АНТАГОНИСТЫ |
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| KR101349925B1 (ko) | 2014-01-14 |
| US20090170956A1 (en) | 2009-07-02 |
| CN101139358A (zh) | 2008-03-12 |
| EP2065358A1 (en) | 2009-06-03 |
| EP2065358A4 (en) | 2009-11-25 |
| CA2662737C (en) | 2013-06-11 |
| KR20090048504A (ko) | 2009-05-13 |
| CA2662737A1 (en) | 2008-03-20 |
| JP5250876B2 (ja) | 2013-07-31 |
| AU2007295835B2 (en) | 2012-07-12 |
| AU2007295835A1 (en) | 2008-03-20 |
| EP2065358B1 (en) | 2015-07-08 |
| US7838706B2 (en) | 2010-11-23 |
| JP2010502656A (ja) | 2010-01-28 |
| WO2008031333A1 (fr) | 2008-03-20 |
| RU2451664C2 (ru) | 2012-05-27 |
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