CN101085743A - 含氟烷氧基康普立停衍生物及制法和用途 - Google Patents
含氟烷氧基康普立停衍生物及制法和用途 Download PDFInfo
- Publication number
- CN101085743A CN101085743A CNA2006100273076A CN200610027307A CN101085743A CN 101085743 A CN101085743 A CN 101085743A CN A2006100273076 A CNA2006100273076 A CN A2006100273076A CN 200610027307 A CN200610027307 A CN 200610027307A CN 101085743 A CN101085743 A CN 101085743A
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- Prior art keywords
- fluorine
- compound
- fluoroalkoxy
- amino
- phenyl aldehyde
- Prior art date
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- 239000011737 fluorine Substances 0.000 title claims abstract description 35
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- -1 alkoxy combretastatin derivative Chemical class 0.000 title claims description 94
- 238000002360 preparation method Methods 0.000 title claims description 31
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 8
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 8
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Abstract
本发明公开了一类新的康普立停(Combretastatin)衍生物及其制备方法。它具有下列结构式(I),其在天然产物康普立停(Combretastatin)B芳环的4′位引入了含氟烷氧基,同时在它的3′位进行功能性化学修饰,导入氨基、硝基、卤素、烷氧基、磷酸盐、氨基酸侧链等。这些新衍生物具有更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
癌症是目前世界上得病率最高、死亡率最高的疾病之一。癌症极为严重地威胁着人类的生存健康,攻克癌症是全球面临的一项难题。在上个世纪70年代早期,由于人们对癌症的成因一无所知,科学家只好盲目的寻找治疗癌症的药物。1966年,美国国家癌症研究所开始赞助的化学药物筛选计划,逐一测试成千上万种已知可能治疗癌症的化学药品。这项筛选结果加上其他抗癌计划所开发出来的药物,包括氨基甲基叶酸、环磷酰胺,西伯拉丁、氟脲嘧啶、紫杉醇等。这些药物虽然能减轻肿瘤的病况,但是持续用药通常会导致极严重的“多重药物抗药性”,使得继续用药也没有太大的疗效。更糟的是肿瘤最后发展出抗药性,再也无法治疗。
1971年美国福克曼(Folkman)博士最早提出血管新生理论(AngiogenesisTheory),大胆作出如下设想:1)肿瘤的生存需要依靠新生血管的生成,2)肿瘤能够主动刺激这种血管的生成,3)肿瘤能够分泌某种物质诱使血管朝它们生长,并能生长出分枝。实体瘤的生长取决于肿瘤细胞和肿瘤血管内皮细胞这两类细胞的数量,两者相互依存,任何一种细胞群的增减必然会导致另一类细胞群的相应增减。因此,抑制任何一类细胞生长的药物都具有肿瘤治疗作用,前者是以细胞毒药物为主的肿瘤化学治疗,后者是最近倍受关注的抗肿瘤血管生成疗法。实体瘤生长和转移依赖于血管生成,这是20世纪70年代初美国福克曼(Folkman)博士提出的设想,他认为如果抑制肿瘤血管生成,可使肿瘤细胞因缺血、缺氧而部分死亡,从而延缓肿瘤生长和抑制肿瘤转移。目前已经证明,肿瘤的生长必须依赖于血管的生成。体积在1-2mm3以下的瘤体可通过渗透作用从周围组织中获得营养,以维持自身的生存。这时肿瘤生长极为缓慢,因为它的进一步生长必须依赖于新生血管以获得充分的营养供应。肿瘤血管生成包含毛细血管基底膜降解、血管内皮细胞迁移增殖、形成管状结构、基底膜形成、血流贯通等步骤,这一过程既受机体神经内分泌因素等影响,又受肿瘤细胞和肿瘤基质细胞表达的生长因子调控。
肿瘤抗血管生成疗法,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***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***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。同直接杀伤肿瘤细胞的化学治疗相比,血管生成抑制剂抗肿瘤具有明显优势。第一,肿瘤发生时,血管生成已被启动,故具有良好的特异性;疗效显著,药物直接作用于血管内皮细胞,只要阻断单一的血管就可以引起成千上万的癌细胞缺氧死亡,相关研究表明给药两小时以后就会引起缺血部位99%的癌细胞大面积死亡。第二,血管内皮细胞暴露于血流中,药物能直接发挥作用,不直接杀死癌细胞,只是改变细胞的形状或生长速度,剂量小,仅仅为最大耐受量(MTD)的几十分之一,而且由于用药量少疗效高,没有放疗和化疗等治疗方案带来的不良反应。第三,内皮细胞基因表达相对稳定,不易产生耐药性。肿瘤血管内皮细胞的增殖速度较正常组织快几十倍,血管生成抑制剂对快速增殖的肿瘤血管内皮有选择性作用,对正常组织副作用极小,具有很大的优越性。
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。已知风车藤(Combretum)属的植物中有25种。它们在非洲和印度被用于治疗麻风和癌症等。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,化学家皮特·乔治教授(G.Robert Pettit)和四位同事从学名为“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”,皮特教授在《加拿大化学期刊》中写道,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。由佩提特小组最先开展这方面的工作。对combretum属植物进行深入研究,提纯出一系列抗癌活性的菲,芪和二苄苯的衍生物。其中Combretastatin A-1和A-4(简写为CA-1和CA-4,结构式见通式I I)是目前为止,所知的此类化合物中作用最强的微管蛋白生长抑制剂(US 5,561,122;WO 9935150)。
虽然Combretastatins类化合物的发现时间不长,但是却引起广泛的研究兴趣。这不仅是因为它们具有较高的抗肿瘤活性,而且它们是一类结构较为简单的抑制微管聚合和阻断肿瘤新生血管的小分子天然产物。CA-4的作用机制研究表明,A环和B环分别作用于微管蛋白的α和β链上的两个相离的位点,从而引起肿瘤血管内皮细胞的凋亡。CA-4通过抑制微管蛋白集聚来进攻新生血管进一步消灭肿瘤,这种新生血管可提供肿瘤生长所必需的氧气和营养物质。
CA-4能够进入癌细胞的内皮细胞。在肿瘤内部,内皮细胞是发育不成熟的,相对与其他的正常体细胞而言很容易受到CA-4的激发。一旦CA-4进入内皮细胞内部,内皮细胞的结构就受到CA-4的破坏,其外部形态发生变化,由原来的扁平状态变成椭球状态,从而有效地堵塞了提供肿瘤细胞养分的新生毛细血管,导致肿瘤部位大面积的缺血性坏死,最终导致癌细胞的凋亡。从以往的实验和临床来看这些部位传统的抗癌药物根本没有办法进入。这一理论在CA-4的I期临床实验中得到证实。对于各个不同的肿瘤患者通过CA-4的治疗,4-6小时之内,他们的肿瘤附近的血流量明显减少。95%以上的癌细胞坏死。CA-4还可以治疗其它血管增生性疾病,包括糖尿病型增生性视网膜病变,银屑病,关节炎等疾病,对免疫功能有增强的作用,在治疗艾滋病方面有良好的效果(WO02058535;US 6773702)。
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.2004 Jan 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.)因此对类似CA-4的新衍生物的研发,成为这一领域的热点研究目标。如Oxigene,Inc.公司研发的功能性二苯乙烯衍生物CA-1和CA-4的类似物(US 6,919,324)。
本领域技术人员了解,在生物活性分子中引入氟会影响该分子的活性,但并不能确定是增加其活性还是减少其活性。
如SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.p.A.公司研究了含氟取代的Combretastatin,在其双键桥上引入氟原子(WO 2005/007603 A2),但其活性与CA-4没有大的区别。
因此,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含氟烷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:
Rf是含有1-8个碳原子且具有1-17个氟原子的烷基;
R为氨基、取代氨基、羟基、硝基、卤素、烷氧基、磷酸盐或氨基酸侧链及其药学上可接受的盐。
更佳地,Rf=-CH2F,-CHF2,-CnF2n+1,-CH2CnF2n+1,-CHFCnF2n+1或-CH2CHFCnF2n+1,n表示1-3的整数。
在另一优选例中,所述的Rf和R选自下组:
(a)Rf是含氟甲基,R是羟基,
(b)Rf是含氟甲基,R是氨基或取代氨基,
(c)Rf是含氟甲基,R是磷酸二钠盐或是磷酸铵盐或是磷酸胆碱内式盐,或(d)Rf是含氟甲基,R是-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。
在另一优选例中,所述的Rf和R选自下组:
(a)Rf是含氟乙基,R是羟基,
(b)Rf是含氟乙基,R是氨基或取代氨基,
(c)Rf是含氟乙基,R是磷酸二钠盐或是磷酸铵盐或是磷酸胆碱内式盐,或(d)Rf是含氟乙基,R是-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。
在另一优选例中,所述的Rf和R选自下组:
(a)Rf=-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2或-CF2CF3,R=-OH或-OPO3Na2,或(b)Rf=-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2或-CF2CF3,R=-NH2或-NHCOCH(NH2)CH2OH。
在另一优选例中,Rf=-CHF2,R=-OH。
在另一优选例中,Rf=-CHF2,R=-OPO3Na2。
在另一优选例中,Rf=-CHF2,R=-NH2。
在另一优选例中,Rf=-CHF2,R=-NHCOCH(NH2)CH2OH。
在另一优选例中,Rf=-CH2CF3,R=-OH。
在另一优选例中,Rf=-CH2CF3,R=-OPO3Na2。
在另一优选例中,Rf=-CH2CF3,R=-NH2。
在另一优选例中,Rf=-CH2CF3,R=-NHCOCH(NH2)CH2OH。
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)间甲氧基对羟基苯甲醛III,在相转移催化下,用含氟试剂进行含氟烷基化反应,形成间甲氧基对含氟烷氧基苯甲醛V;
(2)用二苯基膦锂,脱去间甲氧基对含氟烷氧基苯甲醛V间位甲氧基,使转化成羟基,得到间位羟基化的对含氟烷氧基苯甲醛VI;
(3)将间位羟基化的对含氟烷氧基苯甲醛VI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(Wittig)反应,脱保护后,得到通式I化合物。
在另一优选例中,它包括步骤:
(a)对羟基苯甲醛IV,在相转移催化下,用含氟试剂进行含氟烷基化反应,形成对含氟烷氧基苯甲醛VII;
(b)用硝酸和乙酸酐,将对含氟烷氧基苯甲醛VII进行间位硝化反应,得到间位硝基取代的对含氟烷氧基苯甲醛VIII;
(c)将间位硝基取代的对含氟烷氧基苯甲醛VIII与3,4,5-三甲氧基苄基三苯膦叶立德发生Wittig反应,得到通式I化合物。
在另一优选例中,所述的含氟试剂为含氟卤代甲烷或磺酸含氟烷基酯。
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,所述的肿瘤主要包括:肺癌、非小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、***癌、***癌、睾丸癌、结肠癌、 卵巢癌、膀胱癌、子***、黑色素瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、***状癌、***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、***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***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***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、***肉瘤、淋巴肉芽瘤、***瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、***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、***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,其生物活性有了进一步的提高。
附图说明
图1:含氟甲氧基康普立停的合成路线。
图2:含氟乙氧基康普立停的合成路线。
图3:含氟甲氧基康普立停氨基酸衍生物的合成路线。
图4:含氟乙氧基康普立停氨基酸衍生物的合成路线。
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,THF表示四氢呋喃,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-Ser(Ac)表示N-α-9-芴基甲氧羰基丝氨酸衍生物,DCC表示环己基碳二亚胺,HOBt表示1-羟基苯并***,DMF表示二甲基甲酰胺;
aq.HCl表示稀盐酸,aq.NaOH表示稀氢氧化钠,conc.HCl表示浓盐酸,conc.HNO3表示浓硝酸。
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康普立停(Combretastatin)的B芳环4′位烷氧基是个活性作用点,在B芳环的4′位引入含氟烷氧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′位引入含氟烷氧基。
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。
如本文所用,康普立停(Combretastatin)衍生物是如通式II的化合物。
化合物
本发明提供的含氟烷氧基康普立停(Combretastatin)衍生物是在Combretastatin B芳环4′位引入含氟烷氧基,结构如通式I:
其中Rf是含有1-8个碳原子且具有1-17个氟原子的烷基;
R为氨基、取代氨基、羟基、硝基、卤素、烷氧基、磷酸盐或氨基酸侧链及其药学上可接受的盐。
更佳地,Rf=-CH2F,-CHF2,-CnF2n+1,-CH2CnF2n+1,-CHFCnF2n+1或-CH2CHFCnF2n+1,n表示1-3的整数。
优选含氟甲氧基康普立停或含氟甲氧基康普立停氨基酸衍生物,结构如通式I,其中的Rf=-CH2F、-CHF2或-CF3,R=-OH、-OPO3Na2、-NH2或-NHCOCH(NH2)CH2OH;更优选Rf=-CHF2,R=-OH、-OPO3Na2、-NH2或-NHCOCH(NH2)CH2OH。
本发明还优选含氟乙氧基康普立停或含氟乙氧基康普立停氨基酸衍生物,结构如通式I,其中的Rf=-CH2CF2、-CH2CHF2或-CF2CF3,R=-OH、-OPO3Na2、-NH2或-NHCOCH(NH2)CH2OH。
本发明提供的含氟烷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)。
本发明提供的含氟烷氧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,进行含氟烷基化反应;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含氟烷氧基苯甲醛衍生物。然后以这些新的含氟烷氧基苯甲醛衍生物为原料进行硝化、还原、羟基保护、Wittig反应、脱保护、磷酸盐化、氨基酸化等的合成工艺优化,制备了一系列含氟烷氧基康普立停(Combretastatin)衍生物。
(一)制备含氟烷氧基苯甲醛衍生物
4-羟基-3-甲氧基苯甲醛(香兰素)III或对羟基苯甲醛IV,用含氟烷基化试剂,在无机碱和相转移催化剂的作用下,制备4-含氟烷氧基-3-甲氧基苯甲醛V或对含氟烷氧基苯甲醛VII。
所述的含氟烷基化试剂选自含氟卤代烷、磺酸含氟烷基酯,优选氟里昂(F22)或对甲苯磺酸含氟烷基酯。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),优选芐基三乙基氯化铵、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-含氟烷氧基-3-甲氧基苯甲醛V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-含氟烷氧基-3-羟基苯甲醛VI。对含氟烷氧基苯甲醛VII,在乙酸酐作溶剂的条件下,用浓硝酸实施间位的硝化,得到间位硝基取代的对含氟烷氧基苯甲醛VIII。
(二)制备含氟烷氧基康普立停(Combretastatin)衍生物
在有机碱的催化下,4-含氟烷氧基-3-羟基苯甲醛VI和三苯甲基氯反应,得到3位羟基保护的含氟烷氧基苯甲醛衍生物。溴化3,4,5-三甲氧基苄基三苯鳞在正丁基锂的作用下,转变成相应的膦叶立德,和上述3位羟基保护的含氟烷氧基苯甲醛衍生物进行Wittig反应,生成的含氟烷氧基二苯乙烯衍生物,在浓盐酸和三氟乙酸的联合作用下,脱去三苯甲基,得到3’位是羟基的含氟烷氧基康普立停衍生物IX。
同样,4-含氟烷氧基-3-硝基苯甲醛VIII与上述膦叶立德发生Wittig反应,生成3’位是硝基的含氟烷氧基康普立停衍生物X。
(三)制备含氟烷氧基康普立停的磷酸盐或氨基酸衍生物
如图1或图2所示,上述含氟烷氧基康普立停衍生物IX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,生成含氟烷氧基康普立停的磷酸盐XI。
或者,如图3或图4所示,上述含氟烷氧基康普立停衍生物X的3’位硝基,用还原剂还原成氨基,还原剂优选氯化亚锡、锌粉/乙酸或硫代硫酸钠。然后在N-α-9-芴基甲氧羰基氨基酸衍生物(FmocAA)和环己基碳二亚胺(DCC)以及1-羟基苯并***(HOBt)的作用下,在3-位引入氨基酸侧链,然后在氢氧化钠的作用下,脱保护转换成氨基酸酰胺,得含氟烷氧基康普立停的氨基酸衍生物XII。
R’=氢、苯基或氨基酸侧链,m=1-3的整数。
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含氟烷氧基康普立停(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。
本发明含氟烷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、***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′位引入含氟烷氧基,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
制备对二氟甲氧基苯甲醛:
在装有温度计、机械搅拌、回流冷凝管、导气管的1L四颈烧瓶加入对羟基苯甲醛50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(2.665mol.)的120毫升水溶液,搅拌30分钟,将反应体系加热到65℃,在此温度下通入一氯二氟甲烷(F22)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***(3×300mL)萃取,有机相用水洗至中性,无水MgSO4干燥。减压蒸去***,减压蒸馏得到对二氟甲氧基苯甲醛(85~87℃/10mmHg)。产率95%。1H-NMR(ppm)δ:9.87(1H,s;-CHO);7.70(2H,m;2,6-ArH);7.36(1H,t;J2 H-F=68Hz;-CHF2);6.96(2H,m;3,5-ArH)。
实施例2
制备4-二氟甲氧基-3-甲氧基苯甲醛:
按实施例一,用4-羟基-3-甲氧基苯甲醛62.5克(0.41mol.)代替对羟基苯甲醛,得到4-二氟甲氧基-3-甲氧基苯甲醛(117~120℃/10mmHg)。产率93%。1H-NMR(ppm)δ:9.85(1H,s;-CHO);7.38(1H,t;J2 H-F=69Hz;-CHF2);7.27(1H,m;6-ArH);7.20(1H,m;2-ArH);6.83(1H,m;5-ArH);3.73(3H,s;-OCH3)。
实施例3
制备4-二氟甲氧基-3-羟基苯甲醛:
步骤1,在氩气的保护之下,取4-二氟甲氧基-3-甲氧基苯甲醛61克(0.3mol)加入到三颈瓶中,然后加入乙二醇1 30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***溶液,作为催化剂。反应24小时,TLC跟踪。冷却到室温,加入200ml浓度为15%氢氧化钠水溶液,用300ml的***萃取,分液,用饱和食盐水洗涤,无水硫酸镁干燥,减压蒸去溶剂,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50克(0.2mol)。室温搅拌3-4小时,TLC跟踪。加水中止反应,加入200ml浓度为30%的氢氧化钠溶液后,用300ml***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***萃取,合并***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31.2g(m.p.104~106℃),产率83%。1H-NMR(ppm)δ:9.86(1H,s;-CHO);7.37(1H,t;J2 H-F=72Hz;-CHF2);7.26(1H,m;6-ArH);7.17(1H,m;2-ArH);6.79(1H,m;5-ArH);4.88(1H,s;-OH)。13C-NMR(ppm)δ:191.0(CHO),163.9(t,CHF2),157.2(4-ArC),146.2(3-ArC),130.6(1-ArC),123.5(6-ArC),116.7(2-ArC),116.2(5-ArC)。
实施例4
制备4-二氟甲氧基-3-硝基苯甲醛:
在装有滴液漏斗和机械搅拌的1000毫升三颈瓶中,加入新蒸的对二氟甲氧基苯甲醛72克(0.42mol.)和400毫升醋酐。用冰盐浴冷却,然后慢慢地滴入浓硝酸二氯甲烷溶液,36毫升浓硝酸加50毫升二氯甲烷。保持滴加温度低于5度,约3-4小时滴完。TLC跟踪。随后反应温度可以慢慢地升到室温。继续搅拌2天。
冷却反应瓶至0~5℃,搅拌下加入20%的盐酸,直到沉淀出现停止加酸。再冷却到沉淀完全。过滤得到黄色晶体。用95%的乙醇重结晶,得到淡黄色晶体74克(m.p.88~90℃)产率81%。1H-NMR(ppm)δ:9.92(1H,s;-CHO);7.87(1H,t;J2 H-F=70Hz;-CHF2);7.68(1H,m;6-ArH);7.59(1H,m;2-ArH);7.22(1H,m;5-ArH)。13C-NMR(ppm)δ:194.0(CHO),165.1(t,CHF2),160.2(4-ArC),157.4(3-ArC),137.3(1-ArC),130.2(6-ArC),122.5(2-ArC),120.2(5-ArC)。
实施例5
制备对三氟乙氧基苯甲醛:
在装有温度计、机械搅拌,回流冷凝管的1L四颈烧瓶中,加入对羟基苯甲醛50克(0.41mol)、400ml N,N-二甲基甲酰胺(DMF),5克18-冠-6,搅拌20分钟,分批加入168克碳酸钾粉末(1.22mol.),搅拌30分钟,将反应体系加热到110℃,滴入对甲苯磺酸三氟乙酯115克(0.45mol)的DMF溶液100ml,约1小时滴完,加热到130℃,继续反应3-4小时,TLC跟踪。完成后将体系冷却到0℃。倒入已冷却的600毫升3N盐酸。搅拌后,加入1000毫升***萃取。分出水层,水层再用400毫升***萃取三次。合并醚层,随后,依次用3N盐酸、蒸馏水、饱和食盐水各400毫升洗涤。用无水硫酸镁干燥。除去***,剩余粗产物。随后,减压蒸馏得到对三氟乙氧基苯甲醛(95~97℃/10mmHg)。产率88%。1H-NMR(ppm)δ:9.80(1H,s;-CHO);7.65(2H,m;2,6-ArH);6.83(2H,m;3,5-ArH);4.56(2H,q;J3 H-F=7.2Hz;-CH2CF3)。
实施例6
制备4-三氟乙氧基-3-甲氧基苯甲醛:
按实施例五,用4-羟基-3-甲氧基苯甲醛62.5克(0.41mol.)代替对羟基苯甲醛,得到4-三氟乙氧基-3-甲氧基苯甲醛(126~129℃/10mmHg)。产率83%。1H-NMR(ppm)δ:9.88(1H,s;-CHO);7.27(1H,m;6-ArH);7.20(1H,m;2-ArH);6.83(1H,m;5-ArH);4.48(2H,q;J3 H-F=7.2Hz;-CH2CF3);3.65(3H,s;-OCH3)。
实施例7
制备4-三氟乙氧基-3-羟基苯甲醛:
按实施例三,用4-三氟乙氧基-3-甲氧基苯甲醛70克(0.3mol)代替4-二氟甲氧基-3-甲氧基苯甲醛,得到4-三氟乙氧基-3-羟基苯甲醛(m.p.133~135℃),产率81%。1H-NMR(ppm)δ:9.81(1H,s;-CHO);7.26(1H,m;6-ArH);7.17(1H,m;2-ArH);6.79(1H,m;5-ArH);4.88(1H,s;-OH);4.45(2H,q;J3 H-F=7.2Hz;-CH2CF3)。13C-NMR(ppm)δ:191.0(CHO),157.2(4-ArC),146.2(3-ArC),130.6(1-ArC),126(q,CF3),123.5(6-ArC),116.7(2-ArC),116.2(5-ArC),87(m,CH2)。
实施例8
制备4-三氟乙氧基-3-硝基苯甲醛:
按实施例四,用对三氟乙氧基苯甲醛86克(0.42mol)代替对二氟甲氧基苯甲醛,得到4-三氟乙氧基-3-硝基苯甲醛(m.p.126~127℃),产率78%。1H-NMR(ppm)δ:9.91(1H,s;-CHO);7.28(1H,m;6-ArH);7.20(1H,m;2-ArH);6.77(1H,m;5-ArH);4.46(2H,q;J3 H-F=7.2Hz;-CH2CF3)。13C-NMR(ppm)δ:191.0(CHO),157.2(4-ArC),146.2(3-ArC),130.6(1-ArC),127(q,CF3),123.5(6-ArC),116.7(2-ArC),116.2(5-ArC),89(m,CH2)。
实施例9
制备(Z)-1-(3,4,5-三甲氧基苯基)-2-(3’-羟基-4’-二氟甲氧基苯基)-乙烯(DD8011):
步骤1,在氩气氛下,加入4-二氟甲氧基-3-羟基苯甲醛12.5g(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25.8克,产率91%。1H-NMR(ppm)δ:9.87(s,1H,CHO);7.37(t,1H;J2 H-F=72Hz;-CHF2);7.26(m,2H,Ar-H);7.19(m,15H,Tr-H);6.85(s,1H,Ar-H).
步骤2,在氩气保护下,将溴化三甲氧基苯基亚甲基三苯鳞15g(28.7mmol.)悬浮于30ml 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12.5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。经快速柱层析分离得到15克白色晶体,产率88%。1H-NMR(ppm)δ:7.19(m,15H,Tr-H);6.94(d,1H,2’-H);6.80(dd,1H,6’-H);6.74(d,1H,5’-H);6.55(s,2H,2,6-H);6.52(t,1H;J2 H-F=72Hz;-CHF2)6.47(d,1H,1a-H);6.41(d,1H,1a’-H);3.88(s,3H,4-OCH3);3.71(s,6H,3,5-OCH3)。
步骤3,室温下,取上述Wittig反应产物10g(16.8mmol.),用20ml甲苯溶解。然后滴加37%HCl 4ml,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5.6克,产率95%。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);6.53(t,1H;J2 H-F=72Hz;-CHF2)6.46(d,1H,1a-H);6.40(d,1H,1a’-H);5.51(broad,1H;OH);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3)。
结构如式XIII:
实施例10
制备(Z)-1-(3,4,5-三甲氧基苯基)-2-(3’-氨基-4’-二氟甲氧基苯基)-乙烯(DD8021):
步骤1,在氩气保护下,将溴化三甲氧基苯基亚甲基三苯鳞15g(28.7mmol.)悬浮于30ml 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6.3克(29mmol.)4-二氟甲氧基-3-硝基苯甲醛溶解于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。经快速柱层析分离得到6.6克浅黄色晶体,产率61%。1H-NMR(ppm)δ:7.32(d,1H,2’-H);7.16(dd,1H,6’-H);6.90(d,1H,5’-H);6.78(t,1H;J2 H-F=72Hz;-CHF2);6.64(s,2H,2,6-H);6.49(d,1H,1a-H);6.43(d,1H,1a’-H);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3)。
步骤2,取(Z)-1-(3,4,5-三甲氧基苯基)-2-(3’-硝基-4’-二氟甲氧基苯基)-乙烯4.1克(10.8mmol.)溶解在10毫升丙酮-水(V/V,2∶1)混合溶剂中,加热到50℃,搅拌溶解。然后,加入18.8克硫代硫酸钠,反应混合物回流6小时,TLC板跟踪,反应完成后,冷却到室温,分出有机层,水层用乙酸乙酯50ml×4萃取,合并有机层,用饱和食盐水洗涤,用无水硫酸镁干燥,过滤,旋转蒸发仪上蒸去部分溶剂,冷却后加入石油醚重结晶。得到2.6克浅黄色晶体,产率68.6%。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,1a-H);6.43(d,1H,1a’-H);6.28(t,1H;J2 H-F=72Hz;-CHF2);5.13(broad,2H,NH2);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3)。
结构如式XIV:
实施例11
制备(Z)-1-(3,4,5-三甲氧基苯基)-2-(3’-羟基-4’-三氟乙氧基苯基)-乙烯(DD8031):
按实施例九,用4-三氟乙氧基-3-羟基苯甲醛14.5g(66mmol.)代替4-二氟甲氧基-3-羟基苯甲醛。经三步反应,得到(Z)-1-(3,4,5-三甲氧基苯基)-2-(3’-羟基-4’-三氟乙氧基苯基)-乙烯,总产率79.5%。1H-NMR(ppm)δ:6.93(d,1H,2’-H);6.84(dd,1H,6’-H);6.72(d,1H,5’-H);6.60(s,2H,2,6-H);6.45(d,1H,1a-H);6.38(d,1H,1a’-H);5.51(broad,1H;OH);4.48(2H,q;J3 H-F=7.2Hz;-CH2CF3);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3)。
结构如式XV:
实施例12
制备(Z)-1-(3,4,5-三甲氧基苯基)-2-(3’-氨基-4’-三氟乙氧基苯基)-乙烯(DD8041):
按实施例十,用4-三氟乙氧基-3-硝基苯甲醛14.5g(66mmol)代替4-二氟甲氧基-3-硝基苯甲醛。经二步反应,得到(Z)-1-(3,4,5-三甲氧基苯基)-2-(3’-氨基-4’-三氟乙氧基苯基)-乙烯,总产率43.6%。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,1a-H);6.43(d,1H,1a’-H);5.13(broad,2H,NH2);4.40(2H,q;J3 H-F=7.2Hz;-CH2CF3);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3)。
结构如式XVI:
实施例13
制备(Z)-1-(3,4,5-三甲氧基苯基)-2-(3’-羟基-4’-二氟甲氧基苯基)-乙烯-3’-O-磷酸二钠盐(DD8011DP,结构如式XVII)和(Z)-1-(3,4,5-三甲氧基苯基)-2-(3’-羟基-4’-三氟乙氧基苯基)-乙烯-3’-O-磷酸二钠盐(DD8031DP,结构如式XVIII):
Combretastatin A-4的酚羟基转换成磷酸二钠盐水溶性前药,其典型的反应过程,按照Pettit,G.R.et al.,Anti-Cancer Drug Design1998,13,183-191进行。见图1和图2。
实施例14
制备(Z)-1-(3,4,5-三甲氧基苯基)-2-(3’-氨基-4’-二氟甲氧基苯基)-乙烯-3’-N-丝氨酰胺(DD8021AS,结构如式XIX)和(Z)-1-(3,4,5-三甲氧基苯基)-2-(3’-氨基-4’-三氟乙氧基苯基)-乙烯-3’-N-丝氨酰胺(DD8041AS,结构如式XX).
氨基取代的二苯乙烯衍生物经N-α-9-芴基甲氧羰基丝氨酸衍生物(FmocAA)与氨基发生偶联反应。然后脱保护,形成氨基酸前药。其反应过程由Pettit,G.R.et al.,J.Med.Chem.,2002,46,525-31报道。见图3和图4。
表1
结构式编号 | Rf | R | |
DD8011 | XIII | -CHF2 | -OH |
DD8021 | XIV | -CHF2 | -NH2 |
DD8031 | XV | -CH2CF3 | -OH |
DD8041 | XVI | -CH2CF3 | -NH2 |
DD8011DP | XVII | -CHF2 | -OPO3Na2 |
DD8031DP | XVIII | -CH2CF3 | -OPO3Na2 |
DD8021AS | XIX | -CHF2 | -NHCOCH(NH2)CH2OH |
DD8041AS | XX | -CH2CF3 | -NHCOCH(NH2)CH2OH |
实施例15
体外抗肿瘤活性评估
体外培养的肿瘤细胞经含氟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%
结果显示:含氟甲氧基康普立停衍生物的体外抗肿瘤活性与天然化合物Combretastatin A-4相当。而含氟乙氧基康普立停衍生物比CA-4的活性要大3到30倍。
实施例16
体外新生血管抑制性能评价
按实施例十五的方法,以人脐静脉内皮细胞(HUVEC)为作用对象,考察含氟烷氧基康普立停衍生物的抗新生血管性能。
DD8021 | 0.002 |
DD8031 | 0.001 |
DD8041 | 0.001 |
结果表明:含氟烷氧基康普立停衍生物具有很强的微管蛋白集聚抑制性能,预示着含氟烷氧基康普立停衍生物是一类潜在的肿瘤血管靶向药物。
实施例17
制备含氟烷氧基康普立停冻干粉剂
配方 | 含量(g) |
DD8031DP | 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)
2.如权利要求1所述的化合物,其特征在于,所述的Rf和R选自下组:
(a)Rf是含氟甲基,R是羟基,
(b)Rf是含氟甲基,R是氨基或取代氨基,
(c)Rf是含氟甲基,R是磷酸二钠盐或是磷酸铵盐或是磷酸胆碱内式盐,
或(d)Rf是含氟甲基,R是-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。
3.如权利要求1所述的化合物,其特征在于,所述的Rf和R选自下组:
(a)Rf是含氟乙基,R是羟基,
(b)Rf是含氟乙基,R是氨基或取代氨基,
(c)Rf是含氟乙基,R是磷酸二钠盐或是磷酸铵盐或是磷酸胆碱内式盐,
或(d)Rf是含氟乙基,R是-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。
4.如权利要求1所述的化合物,其特征在于,所述的Rf和R选自下组:
(a)Rf=-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2或-CF2CF3,R=-OH或-OPO3Na2,或(b)Rf=-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2或-CF2CF3,R=-NH2或-NHCOCH(NH2)CH2OH。
7.如权利要求5或6所述的制备方法,其特征在于,所述的含氟试剂为含氟卤代甲烷或磺酸含氟烷基酯。
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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CN103012248A (zh) * | 2013-01-11 | 2013-04-03 | 浙江大德药业集团有限公司 | 氨基康普立停衍生物的合成及其作为口服抗肿瘤药物的应用 |
CN102245560B (zh) * | 2008-10-15 | 2014-04-16 | 上海华理生物医药有限公司 | 一种乙氧基二苯乙烷衍生物及其制备方法和用途 |
CN104447598A (zh) * | 2013-09-18 | 2015-03-25 | 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 |
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CA2314238C (en) * | 1998-01-09 | 2008-09-02 | Arizona Board Of Regents, A Body Corporate, Acting On Behalf Of Arizona State University | Synthesis of combretastatin a-4 prodrugs and trans-isomers thereof |
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JP2008514614A (ja) * | 2004-09-24 | 2008-05-08 | アリゾナ・ボード・オブ・リージェンツ・ア・ボディ・コーポレート・オブ・ザ・ステート・オブ・アリゾナ・アクティング・フォー・アンド・オン・ビハーフ・オブ・アリゾナ・ステート・ユニバーシティ | ハロコンブスタチンとその合成の方法 |
US20060276440A1 (en) * | 2005-01-03 | 2006-12-07 | An Wenqian F | Treatment of inflammatory disorders |
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AU2006344313A1 (en) | 2007-12-13 |
JP2009539779A (ja) | 2009-11-19 |
CA2660760C (en) | 2013-01-08 |
EP2025661B1 (en) | 2011-03-16 |
DE602006020787D1 (de) | 2011-04-28 |
KR101321960B1 (ko) | 2013-10-25 |
ES2363716T3 (es) | 2011-08-12 |
RU2008153041A (ru) | 2010-07-20 |
EP2025661A4 (en) | 2010-07-28 |
US7786098B2 (en) | 2010-08-31 |
JP5100749B2 (ja) | 2012-12-19 |
AU2006344313B2 (en) | 2012-07-26 |
CA2660760A1 (en) | 2007-12-13 |
AU2006344313B8 (en) | 2012-12-06 |
KR20090023465A (ko) | 2009-03-04 |
EP2025661A1 (en) | 2009-02-18 |
RU2417216C2 (ru) | 2011-04-27 |
DK2025661T3 (da) | 2011-06-14 |
US20080306027A1 (en) | 2008-12-11 |
WO2007140662A1 (fr) | 2007-12-13 |
CN101085743B (zh) | 2012-02-15 |
ATE501999T1 (de) | 2011-04-15 |
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