CN111662250A - 季铵化修饰紫杉烷衍生物、其药物组合物、其合成途径和用途 - Google Patents
季铵化修饰紫杉烷衍生物、其药物组合物、其合成途径和用途 Download PDFInfo
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- CN111662250A CN111662250A CN201910162557.8A CN201910162557A CN111662250A CN 111662250 A CN111662250 A CN 111662250A CN 201910162557 A CN201910162557 A CN 201910162557A CN 111662250 A CN111662250 A CN 111662250A
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Abstract
本发明公开了新一类紫杉烷衍生物,其合成途径,其药物组合物及其在制备抗肿瘤方面药物的用途。该类紫杉烷衍生物是将紫杉烷与主动靶向分子—胆碱或甜菜碱通过一定的连接基团发生羟基取代反应而制得,具有良好的水溶性,具有一定的肿瘤靶向性,在肿瘤组织中可代谢为紫杉醇或多西紫杉醇,作为前药策略,用作有效的抗肿瘤药物。相对于紫杉醇,同等剂量下肿瘤抑制率相当,但不破坏免疫系统,毒性显著降低。
Description
技术领域
本发明属于医药技术领域,具体涉及一类新的紫杉烷类衍生物,所述衍生物不仅具有良好的水溶性,同时具有一定的肿瘤靶向性,相比同等剂量紫杉醇,肿瘤抑制率相当,但不破坏免疫系统,毒性明显降低,并且对紫杉醇耐药肿瘤敏感性提高,可用作高效低毒的抗肿瘤药物。
背景技术
癌症是威胁人类健康的第二大疾病,从全球情况看,近六分之一的死亡由癌症造成,癌症负担不断加重。据世界卫生组织(WHO)发布的《世界癌症报告》,到2035年,全球肿瘤患者可能达到2400万人,在20年间增加近五成,受人口增长和老龄化影响,发展中国家的癌症数量不断攀升,全球60%的病例发生在非洲、亚洲和中美洲及南美洲地区,并且占全世界癌症死亡数的70%,而中国新增癌症病例约占全球的20%,癌症死亡病例约占全球25%。最新的癌症流行病学调查显示,在中国每天约为1万人确诊癌症,平均每分钟就有7人确诊。面临当前日益严峻的癌症发病形势,肿瘤的治疗成为当今疾病治疗领域的世界性难题。
抗肿瘤药物作为癌症治疗的重要方法之一,近年来呈现快速发展趋势,每年各类机构针对不同适应症、不同靶点进行大量的抗肿瘤药物开发。开发疗效高、广谱性强、副作用小的抗肿瘤药物是医药界的新药研发课题的焦点。
紫杉醇作为一个具有抗癌活性的二萜生物碱类化合物,1992年底被美国FDA批准用于抗晚期癌症的治疗,是继阿霉素和顺铂之后最成功的抗癌药物,其化学结构新颖复杂、生物活性广泛而显著、作用机制全新独特、自然资源珍贵奇缺,它是目前已发现的最优秀的天然抗癌药物之一,也是近三十年来药物开发最伟大发现之一。紫杉醇抗瘤谱广,疗效显著,广泛用于非小细胞肺癌、乳腺癌、卵巢癌,及其食管癌、头颈部癌、胃癌等的治疗。然而,紫杉醇的低水溶性和高细胞毒性限制了其临床广泛应用。紫杉醇本身的水溶性很差,其在水中的溶解度小于0.004mg/mL,目前临床上使用的紫杉醇注射液是用聚氧乙烯蓖麻油:无水乙醇(1:1)作为溶媒,极易于在体内发生严重的过敏反应;其次,紫杉醇作为一类细胞毒类抗肿瘤药物,具有骨髓抑制、神经毒性、心血管毒性、肝脏损伤等诸多不良反应。紫杉醇上述缺陷为紫杉醇的后续开发留下了广阔的空间。
临床需求是新药研发的核心追求,为了提高紫杉醇的溶解性,减少紫杉醇对病人的毒副作用,国内外就紫杉醇的新技术与新剂型开展了大量研究。研究热点主要分为两个方向:一是合成能改变紫杉醇溶解性,降低其细胞毒性的衍生物;二是制备紫杉醇的新型制剂。目前,在紫杉醇新型给药系统方面取得了一定的成果,占据市场的主流产品主要有紫杉醇脂质体和紫杉醇白蛋白纳米制剂两种新型制剂在一定程度上克服了水溶性低的难题,并且降低了药物的毒性,提高了抗肿瘤效果。然而,对于紫杉醇脂质体,由于紫杉醇在水相和脂相的溶解度都比较低,长期放置紫杉醇容易从脂质体或脂质纳米粒中析出,继而形成沉淀,使得脂质体和纳米粒制剂缺乏长期稳定性,给临床应用带来不便;对于紫杉醇白蛋白纳米制剂,利用人源性白蛋白作为载体,具有微生物污染及免疫抵抗等风险。因此,为了克服上述障碍,本领域迫切需要开发合成一种既能改变其溶解性,也能降低细胞毒性,抗肿瘤效果更好的紫杉醇衍生物。胆碱,是一类季铵碱,极性非常大。据文献报道胆碱对于细胞维持正常的生理功能起着至关重要的作用,胆碱的缺乏会诱发机体产生病理变化。它作为人体必需营养素具有如下生理功能:它是构成细胞膜的重要成分,也是甘氨酸、甜菜碱、乙酰胆碱、血小板活化因子等体内重要代谢物的前体物质;参与信号传导,促进脑发育;调控细胞凋亡;胆碱是肝脏分泌极低密度脂蛋白所必需的物质,从而有利于降低血清胆固醇,维护肝胆功能等。胆碱作为甲基供体,还与叶酸、甜菜碱及其他B族维生素一起参与一碳代谢,参与核酸的合成,影响DNA的甲基化。并且在许多文献报道中,胆碱及其衍生物作为肿瘤的潜在生物标志物,较正常组织细胞,肿瘤组织存在高水平的分布,可能由于肿瘤细胞具有快速增殖的特性,往往会从体液中主动大量摄取该营养物质物质以满足其增殖需求,因此,它对胆碱的吸收利用远大于正常细胞。
本发明基于前药修饰策略,将胆碱,或取代胆碱,或甜菜碱,或取代甜菜碱,与紫杉烷类化合物结合,不仅可以提高其水溶性,而且同时也提高药物向肿瘤组织的主动转运,延长其在肿瘤靶区域作用时间,降低正常细胞毒性,从而提高药物的治疗指数。胆碱和甜菜碱作为修饰分子具有许多独特的优点,如相对分子量小、无免疫原性、廉价易得、稳定性好、与药物分子之间化学键连接简单易行,靶向应用范围广泛等。
发明内容
本发明提供一类具有下列通式(Ⅰ)所示的紫杉烷衍生物及其药学上可接受的盐:
(Ⅰ)式中:
R1为苯甲酰基,或叔丁氧酰基,或甜菜碱酰基或取代的甜菜碱酰基,或为碳酸酯键、磷酸酯键、二酸酯键、醚键或磺酸酯键连接的胆碱或取代的胆碱;R2为氢或甲基或乙酰基;R3为氢,或甲基,或乙酰基,或甜菜碱酰基或取代的甜菜碱酰基,或为碳酸酯键、磷酸酯键、二酸酯键、醚键或磺酸酯键连接的的胆碱;R4为氢,或甜菜碱酰基或取代的甜菜碱酰基,或为碳酸酯键、磷酸酯键、二酸酯键、醚键或磺酸酯键连接的胆碱或取代的胆碱;R5为氢或甜菜碱酰基或为取代的甜菜碱酰基,或为碳酸酯键、磷酸酯键,二酸酯键、醚键或磺酸酯键连接的胆碱或取代的胆碱。其中,C2’位羟基为(RS)-、(S)-、(R)-构型,(Ⅰ)式中胆碱的C1,C2位在具有手性的情况下,其构型可以为(RS)-、(S)-、(R)-。
本发明也提供了上述紫杉烷衍生物及其药学上可接受的盐在制备抗肿瘤药物中的应用。所述的肿瘤为肺癌、卵巢癌、乳腺癌、结肠癌或肝癌。也包含一种药物组合物,其含有治疗有效量的所述的紫杉烷衍生物及其药学上可接受的盐以及药学上可接受的载体。
综上所述,本发明提供新一类紫杉烷衍生物及其药学上可接受的盐,其制备方法、药物组合物以及其在制备抗肿瘤药物中的用途。
本发明所要解决的技术问题在于克服紫杉醇或多西紫杉醇的上述不足,对其进行结构修饰,提供如下技术方案:
本发明技术方案的第一方面是提供了下列化学结构所示的紫杉烷衍生物及其药学上可接受的盐:
该化合物的结构通式为:
所述紫杉烷衍生物中,
为紫杉烷类化合物,包括紫杉醇、多西紫杉醇、卡巴他赛等。该所述化合物使用碳酸酯键、磷酸酯键等作为连接部分,将靶向分子胆碱,或甜菜碱,或其类似物和抗肿瘤药物紫杉醇、多西紫杉醇、卡巴他赛部分的自由羟基偶联,得到季铵化修饰的紫杉烷衍生物。本发明提供的季铵化修饰紫杉烷类衍生物,由于肿瘤细胞对胆碱的吸收利用远大于正常细胞,从而使该衍生物能被肿瘤细胞主动摄取,在肿瘤部位聚集,进而到达治疗肿瘤的效果同时减弱毒性,可以制成更低毒和更有效的抗肿瘤药物。本发明提供的胆碱化和甜菜碱化修饰紫杉烷类衍生物及其抗肿瘤用途是本发明人的创新,首次公开发表。
本发明所述的紫杉烷衍生物(化合物(Ⅰ)),胆碱或甜菜碱结合紫杉烷类化合物自由羟基的部位不限于2’位,也可以同紫杉烷的7位羟基进行反应,本领域技术人员都了解,2’位和7位羟基均有一定的亲核性,都可实现与一步反应后得到的酰氯发生取代反应,并且在实验中发现2’位羟基有非常好的的区域选择性,与文献报道一致。若想实现7位与胆碱结合,可将2’位羟基通过硅醚化试剂保护,再进行后续的取代反应。
本发明所述的紫杉烷类化合物不限于紫杉醇、多西紫杉醇、卡巴他赛,本领域技术人员都了解紫杉烷类化合物有共同的母核骨架结构,具有相类似的抗肿瘤作用,并且均有2’位和7位羟基与胆碱或甜菜碱进行反应,有相应的反应条件和结果。
本发明所述的化合物的连接基团不限于碳酸酯键,也可以是饱和的碳链,芳环,磺酰基、磷酸酯、二酸酯和醚键等。从化学角度—易于连接和断开考虑,碳酸酯和酰基酯键是最好的选择。
上述式(I)的紫杉烷衍生物中,优选地,胆碱和甜菜碱化修饰紫杉醇衍生物、多西紫杉醇衍生物为下列结构:
本发明要解决的技术问题的第二方面是提供这种新的紫杉烷衍生物的制备方法。
本发明的化合物通过如下反应路线制备
本发明解决的技术问题的第三方面是提供一种药物组合物,其中包括作为活性成分的化合物A、B、C、D、E或其他胆碱化修饰的紫杉烷类化合物、及其药学上可接受的盐以及药学上可接受的载体或赋形剂。
本发明的部分化合物分子中含有碱性基团,可如本专业公认的那样,通过酸处理,转化成药学上可接受的盐。这类成盐的例子包含无机酸盐如盐酸盐、氢溴酸盐、硫酸盐或硫酸氢盐、硝酸盐、磷酸盐或磷酸氢盐等以及有机酸盐如甲酸盐、乙酸盐、苯甲酸盐、丁二酸盐、富马酸盐、马来酸盐、乳酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、葡糖酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐等。
该类化合物可根据本领域公知的方法制备不同的非肠道给药剂型,适于人或动物使用。例如,将本发明化合物制成注射用制剂,如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂,这种制剂可以是含水或非水的,可含一种和多种药效学上可接受的载体、稀释剂、防腐剂、表面活性剂、助溶剂、缓冲剂、pH调节剂。这些辅料都是本领域常用的。为达到用药目的,增强治疗效果,本发明药物或药物组合物可用任何公知的给药方法给药。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用,当本发明的化合物与其他治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明解决的技术问题第四方面是提供所述的季铵化修饰紫杉烷衍生物及其组合物用于制备抗肿瘤药物的用途,本发明所述的肿瘤优选肺癌、乳腺癌、卵巢癌、肝癌、结肠癌、胃癌等,但不限于上述肿瘤。
附图说明
图1紫杉醇衍生物A对小鼠C26结肠癌的生长抑制作用
图2紫杉醇衍生物A对C26结肠癌小鼠免疫系统的影响
图3紫杉醇衍生物A对小鼠EMT6乳腺癌的生长抑制作用
图4紫杉醇衍生物A对EMT6乳腺癌小鼠免疫系统的影响
图5紫杉醇衍生物A对小鼠Lewis肺癌的生长抑制作用
具体实施方式
缩写词:
TEA:三乙胺
DCM:二氯甲烷
本发明公开了一类季铵化修饰的紫杉烷衍生物,含有它们的盐、溶剂合物、前药与药物组合物的应用,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
下面结合具体实施方式,进一步阐述本发明:
实施例1
步骤1 2-((氯甲酰基)氧基)-N,N,N-三甲基-1-铵的制备
在2-羟基-N,N,N-三甲基-1-铵(10.0g,96.15mmol)的二氯甲烷(150ml)溶液中加入三乙醇胺(24.2g,240mmol)。在0℃和N2的条件下,加入碳酸三氯甲基酯(14.23g,48.075mmol)的二氯甲烷溶液(100ml),搅拌45分钟进行充分的反应。浓缩混合物,不经进一步纯化直接使用。
步骤2胆碱化紫杉醇衍生物(紫杉醇衍生物A)的制备
在0℃条件下在2-((氯甲酰基)氧基)-N,N,N-三甲基-1-铵(348mg,2.1mmol)的二氯甲烷溶液(10ml)溶液中加入紫杉醇(1.8g,2.1mmol)。在N2条件下,将混合物在室温下搅拌12小时,反应完成后,过滤混合物。浓缩滤液,通过制备型HPLC纯化,得到500mg白色固体。
1H NMR(400MHz,DMSO-d6)δppm:9.87(s,1H),8.55(s,0.56H),8.02-7.93(m,4H),7.79-7.73(m,1H),7.69(t,J=7.4Hz,2H),7.56(t,J=7.3Hz,1H),7.53-7.43(m,6H),7.17(ddd,J=8.5,5.9,2.6Hz,1H),6.29(s,1H),5.83(t,J=8.8Hz,1H),5.48(t,J=7.0Hz,2H),5.41(d,J=7.2Hz,1H),4.90(d,J=10.1Hz,2H),4.62(s,3H),4.09(dd,J=10.7,6.8Hz,1H),4.00(q,J=8.4Hz,2H),3.81(dt,J=9.2,4.2Hz,1H),3.70(dt,J=8.8,4.2Hz,1H),3.55(d,J=7.2Hz,1H),3.12(s,9H),2.31(dt,J=21.5,7.8Hz,1H),2.21(s,3H),2.15-2.07(m,3H),1.81(d,J=11.4Hz,3H),1.70(ddd,J=34.0,20.5,9.3Hz,2H),1.49(s,3H),1.40(dd,J=15.5,9.1Hz,1H),1.12-0.94(m,6H).
实施例2
甜菜碱化紫杉烷衍生物E的合成路线
实验过程
步骤A
N-2-氯羰基甲基-N,N,N-三甲基氯化铵(2)
将干燥好的甜菜碱盐酸盐加入到(450mg,3.1mmol)加入到氯化亚砜(0.6mL,8mmol)中并加热至75℃。停止放气之后得到黄色粘稠液体。加入热甲苯(80℃,3mL),充分搅拌溶液,倒出上层甲苯相。为了除去氯化亚砜,重复该过程六次,最后的甲苯悬浮液用于下一步反应。
步骤B
(2aR,4aS,6R,9S,11S,12S,12bS)-12b-乙酰氧基-9-(((2R)-3-氨基-2-羟基-3-苯基丙酰基)氧基)-4,6,11三羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二-1氢-7,11-甲环癸[3-4]苯并[1,2-b]氧杂-12-苯甲酸酯(4):
将(2aR,4aS,6R,9S,11S,12S,12bS)-12b乙酰氧基-9-(((2R)-3-((叔丁氧基羰基)氨基)-2-羟基-3-苯基丙酰基)氧基)-4,6,11三羟基甲基-4a,8,13,13四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二-1氢-7,11-甲环癸[3,4]苯并[1,2-b]氧杂-12-苯甲酸酯(2.34g,2.9mmol)溶解在25mL的浓甲酸中,将溶液在室温下搅拌4小时。接下来,减压蒸馏出甲酸,得到(2aR,4aS,6R,9S,11S,12S,12bS)-12b乙酰氧基-9-((2R)-3-氨基-2-羟基-3-苯基丙酰基)氧基)-4,6,11-三羟基-4a,8,13,13四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二-1氢-7,11-甲环癸[3-,4]苯并[1,2-b]氧杂-12-苯甲酸酯2.35g白色固体。
步骤C
在氮气冰浴的条件下,向N-2-氯羰基甲基-N,N,N-三甲基氯化铵(2.35g,粗品)的二氯甲烷溶液(10mL)中加入(2aR,4aS,6R,9S,11S,12S,12bS)-12b乙酰氧基-9-((2R)-3-氨基-2-羟基-3-苯基丙酰基)氧基)-4,6,11-三羟基-4a,8,13,13四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二-1氢-7,11-甲环癸[3-,4]苯并[1,2-b]氧杂-12-苯甲酸酯,和4-(二甲氨基)吡啶(878mg,8.7mmol),将混合物在室温下搅拌12小时后过滤混合物,浓缩滤液,通过制备型HPLC纯化,得到所需产物400mg白色固体。
Mass Spectrum(ESI)m/z=807.3(M+).
1H NMR(400MHz,DMSO-d6):δ9.30(d,J=8.9Hz,1H),7.99(d,J=7.4Hz,2H),7.70(t,J=7.3Hz,1H),7.61(t,J=7.6Hz,2H),7.45-7.33(m,4H),7.28(t,J=7.2Hz,1H),6.29(d,J=5.0Hz,1H),5.92(t,J=8.9Hz,1H),5.43(d,J=7.2Hz,1H),5.32(dd,J=8.8,5.6Hz,1H),5.10(s,1H),5.07-4.85(m,3H),4.57(s,1H),4.44(s,1H),4.17(t,J=9.1Hz,2H),4.03(q,J=8.3Hz,3H),3.69(d,J=7.1Hz,1H),3.17(s,11H),2.37-2.20(m,5H),2.01(dd,J=15.2,9.4Hz,1H),1.83(dd,J=15.2,8.9Hz,1H),1.78-1.61(m,5H),1.51(d,J=14.4Hz,3H),1.07-0.95(m,6H).
药理实验
实验例1紫杉醇衍生物A体外抗肿瘤检测
MTT法测定肿瘤细胞存活率
将对数生长期的细胞用胰酶消化后,配制成一定浓度的单细胞悬液,根据细胞生长速度的差异,按1500-3000个/孔接种于96孔板,每孔加入细胞悬液100μl。次日加入含不同浓度药物及相应溶剂对照的新鲜培养基,每孔加100μl(DMSO终浓度<0.1%),每种受试化合物设4个剂量组(0.05,0.5,5,50μmol/L)每组设三个平行孔。于37℃,5%CO2继续培养96h后弃上清,每孔加入200μL新鲜配制的含0.5mg/mL MTT的无血清培养基。继续培养4h,弃上清,每孔加入200μL DMSO溶解MTT甲簪沉淀,微型振荡器振荡混匀后,酶标仪在检测波长570nm条件下测定光密度值(OD),以溶剂对照处理的肿瘤细胞为对照组,按下列公式计算药物对肿瘤细胞的抑制率,并按中效方程计算IC50:
紫杉醇衍生物A体外抗肿瘤活性结果见表1、表2、表3
表1紫杉醇衍生物A MTT筛选结果-1
Taxol-Choline:紫杉醇衍生物A;MGC-803,BGC823,HGC27:人胃癌细胞株;NCI-H1975,NCI-H1650,A549:人非小细胞肺癌细胞株:NCI-H460:人大细胞肺癌细胞株;A549/Faxol:人耐紫素细胞非小细胞肺癌细胞株;U-87MG,T98G:人神经胶质瘤细胞株
表2紫杉醇衍生物A MTT筛选结果-2
Taxol-Choline:紫杉醇衍生物A;SW1990,Mia-PaCa2,Capan2,BxPC3:人胰腺癌细胞株;HCT15,HCT-8,DLD-1:人结直肠癌细胞株;SW48,HCT116:人结肠癌细胞株;A2780:人卵巢癌细胞株
表3紫杉醇衍生物A MTT筛选结果-3
Taxol-Choline:紫杉醇衍生物A;A498,ACHN:人肾癌细胞株;HK2:人肾近曲小管上皮细胞株;LO2:人正常肝细胞株;MCF-7,MDA-MB-231:人乳腺癌细胞株;MCF-7/Taxol:耐紫素的人乳腺癌细胞株;Be17402,Huh-7,HepG2:人肝癌细胞株;Be17402/5-FU:耐五氟尿嘧啶的人肝癌细胞
实验例2紫杉醇衍生物A体内抗小鼠结肠癌C26效果
小鼠结肠癌移植瘤C26实验
KM小鼠(16~18g),雄性,无菌条件下取传代接种后7d、生长良好的腹水肿瘤细胞,用无菌生理盐水稀释,调整细胞密度至5×107个/ml,取0.2ml接种于小鼠腋窝皮下。次日随机分组并给药,对照组每日口服灌胃蒸馏水,每20g小鼠灌胃0.4ml,每日一次;Taxol(紫素)配制成2.5mg/ml,每20g小鼠腹腔注射给药0.2ml,共给药1次;受试药(紫杉醇衍生物A)组分别配制成1.44,2.88,4.32mg/ml浓度的药液,每20g小鼠灌胃给药0.2ml,每日给药一次,连续给药10日。实验结束时将小鼠脱臼处死,然后剥离肿瘤,称重并拍照。最后计算肿瘤抑制率。
体内抗肿瘤活性效果及对免疫系统和血细胞的影响见表4-8和图1-2。
表4紫杉醇衍生物A对小鼠C26结肠癌的生长抑制作用
*p<0.05,**p<0.01,***p<0.001,与溶剂对照组比较;△△p<0.01,△△△p<0.001,与紫素组比较。紫杉醇衍生物A:28.8mg/kg与紫素25.0mg/kg等摩尔浓度。
表5紫杉醇衍生物A对C26结肠癌小鼠脾指数及胸腺指数的影响
*p<0.05,**p<0.01,***p<0.001,与溶剂对照组比较;△△△p<0.001,与紫素组比较。
表6紫杉醇衍生物A对C26结肠癌小鼠外周血计数的影响
*p<0.05,**p<0.01,***p<0.001,与溶剂对照组比较;Δp<0.05,ΔΔΔp<0.001,与紫素组比较。
WBC:白细胞计数LYM%:淋巴细胞比率MON%:单核细胞比率NEUT%:中性粒细胞比率
表7紫杉醇衍生物A对C26结肠癌小鼠外周血计数的影响
*p<0.05,**p<0.01,***p<0.001,与溶剂对照组比较;Δp<0.05,ΔΔp<0.01,与紫素组比较。
RBC:红细胞计数HGB:血红蛋白HCT:红细胞比容MCV:红细胞平均容积MCH:红细胞平均血红蛋白含量MCHC:红细胞平均血红蛋白浓度RDW:红细胞分布宽度
表8紫杉醇衍生物A对C26结肠癌小鼠外周血计数的影响
*p<0.05,**p<0.01,***p<0.001,与溶剂对照组比较;Δp<0.05,与紫素组比较。
PLT:血小板计数PCT:血小板比积MPV:血小板平均体积PDW:血小板体积分布宽度
实验例3紫杉醇衍生物A体内抗小鼠乳腺癌EMT6效果
小鼠乳腺癌移植瘤EMT6实验
KM小鼠(19~21g),雄性,无菌条件下取传代接种后7d、生长良好的腹水肿瘤细胞,用无菌生理盐水稀释,调整细胞密度至5×107个/ml,取0.2ml接种于小鼠腋窝皮下。次日随机分组并给药,对照组每日口服灌胃蒸馏水,每20g小鼠灌胃0.4ml,每日一次;Taxol(紫素)配制成2.5mg/ml,每20g小鼠腹腔注射给药0.2ml,共给药1次;受试药(紫杉醇衍生物A)组分别配制成1.44,2.88,4.32mg/ml浓度的药液,每20g小鼠灌胃给药0.2ml,每日给药一次,连续给药10日。实验结束时将小鼠脱臼处死,然后剥离肿瘤,称重并拍照。最后计算肿瘤抑制率。
体内抗肿瘤活性效果及对免疫系统和血细胞的影响见表9-13和图3-4。
表9紫杉醇衍生物A对小鼠EMT6乳腺癌的生长抑制作用
*p<0.05,与溶剂对照组比较;△△p<0.01,△△△p<0.001,与紫素组比较。
紫杉醇衍生物A 28.8mg/kg与紫素25.0mg/kg等摩尔浓度。
表10紫杉醇衍生物A对EMT6乳腺癌小鼠脾指数及胸腺指数的影响
**p<0.01,***p<0.001,与溶剂对照组比较;ΔΔp<0.01,ΔΔΔp<0.001,与紫素组比较。
表11紫杉醇衍生物A对EMT6乳腺癌小鼠外周血计数的影响
*p<0.05,**p<0.01,***p<0.001,与溶剂对照组比较;Δp<0.05,ΔΔp<0.01,ΔΔΔp<0.001,与紫素组比较。
WBC:白细胞计数LYM%:淋巴细胞比率MON%:单核细胞比率NEUT%:中性粒细胞比率
表12紫杉醇衍生物A对EMT6乳腺癌小鼠外周血计数的影响
*p<0.05,**p<0.01,与溶剂对照组比较;Δp<0.05,与紫素组比较。
RBC:红细胞计数HGB:血红蛋白HCT:红细胞比容MCV:红细胞平均容积MCH:红细胞平均血红蛋白含量MCHC:红细胞平均血红蛋白浓度
RDW:红细胞分布宽度
表13紫杉醇衍生物A对EMT6乳腺癌小鼠外周血计数的影响
*p<0.05,***p<0.001,与溶剂对照组比较:Δp<0.05,ΔΔp<0.01,ΔΔΔp<0.001,与紫素组比较。
PLT:血小板计数PCT:血小板比积MPV:血小板平均体积PDW:血小板体积分布宽度
实验例4紫杉醇衍生物A体内抗小鼠肺癌Lewis效果
小鼠肺癌移植瘤Lewis实验
KM小鼠(18~20g),雄性,无菌条件下取传代接种后7d、生长良好的腹水肿瘤细胞,用无菌生理盐水稀释,调整细胞密度至5×107个/ml,取0.2ml接种于小鼠腋窝皮下。次日随机分组并给药,对照组每日口服灌胃蒸馏水,每20g小鼠灌胃0.4ml,每日一次;Taxol(紫素)配制成2.5mg/ml,每20g小鼠腹腔注射给药0.2ml,共给药1次;受试药组(紫杉醇衍生物A)分别配制成1.44,2.88,5.76mg/ml浓度的药液,每20g小鼠灌胃给药0.2ml,每日给药一次,连续给药7日。实验结束时将小鼠脱臼处死,然后剥离肿瘤,称重并拍照。最后计算肿瘤抑制率。
体内抗肿瘤活性效果及对免疫系统和血细胞的影响见表14-18和图5。
表14紫杉醇衍生物A对小鼠Lewis肺癌的生长抑制作用
**p<0.01,***p<0.001,与溶剂对照组比较。紫杉醇衍生物A 28.8mg/kg与紫素25.0mg/kg等摩尔浓度。
表15紫杉醇衍生物A对Lewis肺癌小鼠脾指数及胸腺指数的影响
*p<0.05,**p<0.01,***p<0.001,与溶剂对照组比较;
表16紫杉醇衍生物A对Lewis肺癌小鼠外周血计数的影响
*p<0.05,**p<0.01,***p<0.001,与溶剂对照组比较;
WBC:白细胞计数LYM%:淋巴细胞比率MON%:单核细胞比率NEUT%:中性粒细胞比率
表17紫杉醇衍生物A对Lewis肺癌小鼠外周血计数的影响
*p<0.05,**p<0.01,***p<0.001,与溶剂对照组比较;
RBC:红细胞计数HGB:血红蛋白HCT:红细胞比容MCV:红细胞平均容积MCH:红细胞平均血红蛋白含量MCHC:红细胞平均血红蛋白浓度
RDW:红细胞分布宽度
表18紫杉醇衍生物A对Lewis肺癌小鼠外周血计数的影响
*p<0.05,**p<0.01,***p<0.001,与溶剂对照组比较;
PLT:血小板计数PCT:血小板比积MPV:血小板平均体积PDw:血小板体积分布。
Claims (6)
1.一类具有下列通式(Ⅰ)所示的紫杉烷衍生物及其药学上可接受的盐:
(Ⅰ)式中:
R1为苯甲酰基,叔丁氧酰基,甜菜碱酰基,取代的甜菜碱酰基,碳酸酯键、磷酸酯键、二酸酯键、醚键或磺酸酯键连接的胆碱或取代的胆碱;
R2为氢,甲基或乙酰基;
R3为氢,甲基,乙酰基,甜菜碱酰基,取代的甜菜碱酰基,或为碳酸酯键、磷酸酯键、二酸酯键、醚键或磺酸酯键连接的胆碱;
R4为氢,甜菜碱酰基,取代的甜菜碱酰基,碳酸酯键、磷酸酯键、二酸酯键、醚键或磺酸酯键连接的胆碱或取代的胆碱;
R5为氢,甜菜碱酰基,取代的甜菜碱酰基,碳酸酯键、磷酸酯键,二酸酯键、醚键或磺酸酯键连接的胆碱或取代的胆碱;
上述的取代基为卤原子,C1-6烷基,C1-7酰基,C3-6环烷基,羟基,不同种类的氨基酸,如丙氨酸,缬氨酸,苏氨酸,天冬氨酸,丝氨酸等任意一种氨基酸。
2.根据权利要求1所述的紫杉烷衍生物及其药学上可接受的盐,其特征在于,C2’位羟基为(RS)-、(S)-、(R)-构型,(Ⅰ)式中胆碱的C1,C2位在具有手性的情况下,其构型可以为(RS)-、(S)-、(R)-。
4.权利要求1-3任一项所述的紫杉烷衍生物及其药学上可接受的盐在制备抗肿瘤药物中的应用。
5.根据权利要求4的应用,其特征在于,所述的肿瘤为肺癌、卵巢癌、乳腺癌、结肠癌或肝癌。
6.一种药物组合物,其特征在于,含有治疗有效量的权利要求1-3任一项所述的紫杉烷衍生物及其药学上可接受的盐以及药学上可接受的载体。
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---|---|---|---|---|
CN112245590A (zh) * | 2020-10-14 | 2021-01-22 | 燕山大学 | 一种基于巯基化甜菜碱修饰的阿霉素衍生物、纳米药物及其制备方法 |
CN114437128A (zh) * | 2022-01-28 | 2022-05-06 | 中国科学院长春应用化学研究所 | 一种胆碱磷酸修饰的紫杉醇药物及其制备方法和应用 |
CN115385875A (zh) * | 2022-07-18 | 2022-11-25 | 中国药科大学 | 一类紫杉醇衍生物及其制备方法和用途 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4942184A (en) * | 1988-03-07 | 1990-07-17 | The United States Of America As Represented By The Department Of Health And Human Services | Water soluble, antineoplastic derivatives of taxol |
US5470866A (en) * | 1992-08-18 | 1995-11-28 | Virginia Polytechnic Institute And State University | Method for the conversion of cephalomannine to taxol and for the preparation of n-acyl analogs of taxol |
CN102872000A (zh) * | 2012-11-02 | 2013-01-16 | 济南爱思医药科技有限公司 | 紫杉化合物类单烷氧基衍生物在制备抗肿瘤药物中的用途 |
CN104086514A (zh) * | 2014-06-19 | 2014-10-08 | 上海应用技术学院 | 紫杉醇衍生物及其制备方法 |
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CN106699699B (zh) * | 2015-07-14 | 2019-01-15 | 北京康辰药业股份有限公司 | 含有三氟异丙基取代的紫杉醇衍生物及其应用 |
WO2017128173A1 (zh) * | 2016-01-28 | 2017-08-03 | 北京和理咨询有限公司 | 紫杉醇或其衍生物的适配子偶合物及其制备方法和应用 |
-
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- 2019-03-05 CN CN201910162557.8A patent/CN111662250B/zh active Active
-
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- 2020-03-05 WO PCT/CN2020/078071 patent/WO2020177748A1/zh active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4942184A (en) * | 1988-03-07 | 1990-07-17 | The United States Of America As Represented By The Department Of Health And Human Services | Water soluble, antineoplastic derivatives of taxol |
US5470866A (en) * | 1992-08-18 | 1995-11-28 | Virginia Polytechnic Institute And State University | Method for the conversion of cephalomannine to taxol and for the preparation of n-acyl analogs of taxol |
CN102872000A (zh) * | 2012-11-02 | 2013-01-16 | 济南爱思医药科技有限公司 | 紫杉化合物类单烷氧基衍生物在制备抗肿瘤药物中的用途 |
CN104086514A (zh) * | 2014-06-19 | 2014-10-08 | 上海应用技术学院 | 紫杉醇衍生物及其制备方法 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112245590A (zh) * | 2020-10-14 | 2021-01-22 | 燕山大学 | 一种基于巯基化甜菜碱修饰的阿霉素衍生物、纳米药物及其制备方法 |
CN114437128A (zh) * | 2022-01-28 | 2022-05-06 | 中国科学院长春应用化学研究所 | 一种胆碱磷酸修饰的紫杉醇药物及其制备方法和应用 |
CN114437128B (zh) * | 2022-01-28 | 2023-12-19 | 中国科学院长春应用化学研究所 | 一种胆碱磷酸修饰的紫杉醇药物及其制备方法和应用 |
CN115385875A (zh) * | 2022-07-18 | 2022-11-25 | 中国药科大学 | 一类紫杉醇衍生物及其制备方法和用途 |
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