CN110950805A - 一种细胞毒性小的氟尿嘧啶前药及其制备方法和应用 - Google Patents
一种细胞毒性小的氟尿嘧啶前药及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了一种细胞毒性小的氟尿嘧啶前药。该该前药具有式Ⅰ结构,式Ⅰ结构如说明书所示,该氟尿嘧啶前药选择性高,降低对正常细胞的杀伤率,且治疗癌症或肿瘤的效果更好。
Description
技术领域
本发明涉及一种用于抗肿瘤药物的衍生物,特别涉及一种细胞毒性小的氟尿嘧啶前药及其制备方法和应用。
背景技术
5-氟尿嘧啶是一种临床上常用的抗菌药,对念珠菌和隐球菌等具有一定的抗菌活性,5-氟尿嘧啶属于抗代谢药物,阻断正常及肿瘤细胞代谢,阻碍DNA合成,从而抑制肿瘤细胞增殖,由于其在阻断肿瘤细胞代谢的同时也阻断正常细胞代谢,因此对正常细胞毒性较大,毒副作用较强,给患者带来更多的痛苦。
发明内容
为了解决以上技术问题,本发明利用正常细胞与肿瘤细胞酶系之间的差异,对5-氟尿嘧啶的化学结构进行改造,使5-氟尿嘧啶与小分子氨基酸结合制备成前药,该前药在肿瘤细胞内的血纤维蛋白溶酶的作用下肽键断裂,释放出药物,选择性强,降低对正常细胞的毒性。
本发明提供了一种细胞毒性小的氟尿嘧啶前药,具体方案如下:
本发明提供了一种细胞毒性小的氟尿嘧啶前药,该前药具有式1结构:
R选自氢、C1-10烷基或取代的C1-10烷基。
进一步地,R为氢或正丙基、异丙基、异丁基、仲丁基中的一种。
本发明还提供了一种氟尿嘧啶前药的制备方法,该方法包括以下步骤:
S1:将氟尿嘧啶、碳酰氯和式2所示的化合物在碱的作用下生成式3所示的化合物;
S2:式3所示的化合物经碱水解、纯化,制得式1所示的化合物;
反应方程式如下:
进一步地,本发明还提供了氟尿嘧啶前药在制备用于癌症或肿瘤的药物中的应用。
进一步地,癌症或肿瘤包括消化道癌、乳腺癌、卵巢癌、绒毛膜癌、子宫颈癌、肝癌、膀胱癌。
本发明还提供了一种用于癌症或肿瘤的制剂,该制剂包括氟尿嘧啶前药和药学上可接受的辅料。
如可以用注射用水配制成水针剂或输液供临床应用,以用于肿瘤化疗的目的。
本发明提供的细胞毒性小的氟尿嘧啶前药选择性高,降低对正常细胞的杀伤率,且治疗癌症或肿瘤的效果更好。
具体实施方式
实施例1-5的结构式见表1.
表1.实施例1-5的结构式
实施例1制备2-(5-氟尿嘧啶-1-羧酰胺)乙酸
2-(5-氟尿嘧啶-1-羧酰胺)乙酸的制备方法如下:
S1:在反应瓶中加入140mg氟尿嘧啶、118.8mg碳酰氯、103mg式2-1所示的甘氨酸乙酯和20mL甲醇,搅拌条件下加入136mg醋酸钠,在80℃油浴锅内搅拌反应2h,监测反应完全后,减压蒸除甲醇,浓缩物采用石油醚/乙酸乙酯为流动相用硅胶柱纯化,制得中间产物2-(5-氟尿嘧啶-1-羧酰胺)乙酸乙酯(式3-1),产率为65.4%;
S2:将中间产物式3-1加入到20mL0.2M的氢氧化钠水溶液中,10℃搅拌,监测反应完全,用0.2M的盐酸调节pH至7,然后边搅拌边加入乙醇,于10℃放置过夜,有固体析出,过滤,滤饼用乙醇洗涤,干燥,即得式1-1[2-(5-氟尿嘧啶-1-羧酰胺)乙酸],产率为63.7%;
实施例2制备2-(N-正丙基-N-正丙基-5-氟尿嘧啶-1-羧酰胺)乙酸
2-(N-正丙基-5-氟尿嘧啶-1-羧酰胺)乙酸的制备方法如下:
S1:在反应瓶中加入140mg氟尿嘧啶、118.8mg碳酰氯、145mg式2-2所示的N-正丙基甘氨酸乙酯和20mL甲醇,搅拌条件下加入136mg醋酸钠,在80℃油浴锅内搅拌反应2h,监测反应完全后,减压蒸除甲醇,浓缩物采用石油醚/乙酸乙酯为流动相用硅胶柱纯化,制得中间产物2-(N-正丙基-5-氟尿嘧啶-1-羧酰胺)乙酸乙酯(式3-2),产率为62.2%;
S2:将中间产物式3-2加入到20mL0.2M的氢氧化钠水溶液中,10℃搅拌,监测反应完全,用0.2M的盐酸调节pH至7,然后边搅拌边加入乙醇,于10℃放置过夜,有固体析出,过滤,滤饼用乙醇洗涤,干燥,即得式1-2[2-(N-正丙基-5-氟尿嘧啶-1-羧酰胺)乙酸],产率为65.3%;
实施例3制备2-(N-异丙基-N-异丙基-5-氟尿嘧啶-1-羧酰胺)乙酸
2-(N-异丙基-5-氟尿嘧啶-1-羧酰胺)乙酸的制备方法如下:
S1:在反应瓶中加入140mg氟尿嘧啶、118.8mg碳酰氯、145mg式2-3所示的N-异丙基甘氨酸乙酯和20mL甲醇,搅拌条件下加入136mg醋酸钠,在80℃油浴锅内搅拌反应2h,监测反应完全后,减压蒸除甲醇,浓缩物采用石油醚/乙酸乙酯为流动相用硅胶柱纯化,制得中间产物2-(N-异丙基-5-氟尿嘧啶-1-羧酰胺)乙酸乙酯(式3-3),产率为62.9%;
S2:将中间产物式3-3加入到20mL0.2M的氢氧化钠水溶液中,10℃搅拌,监测反应完全,用0.2M的盐酸调节pH至7,然后边搅拌边加入乙醇,于10℃放置过夜,有固体析出,过滤,滤饼用乙醇洗涤,干燥,即得式1-3[2-(N-异丙基-5-氟尿嘧啶-1-羧酰胺)乙酸],产率为72.6%;
实施例4制备2-(N-异丁基-N-异丁基-5-氟尿嘧啶-1-羧酰胺)乙酸
2-(N-异丁基-5-氟尿嘧啶-1-羧酰胺)乙酸的制备方法如下:
S1:在反应瓶中加入140mg氟尿嘧啶、118.8mg碳酰氯、159mg式2-4所示的N-异丁基甘氨酸乙酯和20mL甲醇,搅拌条件下加入136mg醋酸钠,在80℃油浴锅内搅拌反应2h,监测反应完全后,减压蒸除甲醇,浓缩物采用石油醚/乙酸乙酯为流动相用硅胶柱纯化,制得中间产物2-(N-异丁基-5-氟尿嘧啶-1-羧酰胺)乙酸乙酯(式3-4),产率为60.1%;
S2:将中间产物式3-4加入到20mL0.2M的氢氧化钠水溶液中,10℃搅拌,监测反应完全,用0.2M的盐酸调节pH至7,然后边搅拌边加入乙醇,于10℃放置过夜,有固体析出,过滤,滤饼用乙醇洗涤,干燥,即得式1-4[2-(N-异丁基-5-氟尿嘧啶-1-羧酰胺)乙酸],产率为66.6%;
实施例5制备2-(N-仲丁基-N-仲丁基-5-氟尿嘧啶-1-羧酰胺)乙酸
2-(N-仲丁基-5-氟尿嘧啶-1-羧酰胺)乙酸的制备方法如下:
S1:在反应瓶中加入140mg氟尿嘧啶、118.8mg碳酰氯、159mg式2-5所示的N-仲丁基甘氨酸乙酯和20mL甲醇,搅拌条件下加入136mg醋酸钠,在80℃油浴锅内搅拌反应2h,监测反应完全后,减压蒸除甲醇,浓缩物采用石油醚/乙酸乙酯为流动相用硅胶柱纯化,制得中间产物2-(N-仲丁基-5-氟尿嘧啶-1-羧酰胺)乙酸乙酯(式3-5),产率为61.3%;
S2:将中间产物式3-5加入到20mL0.2M的氢氧化钠水溶液中,10℃搅拌,监测反应完全,用0.2M的盐酸调节pH至7,然后边搅拌边加入乙醇,于10℃放置过夜,有固体析出,过滤,滤饼用乙醇洗涤,干燥,即得式1-5[2-(N-仲丁基-5-氟尿嘧啶-1-羧酰胺)乙酸],产率为60.8%;
试验例1 5-氟尿嘧啶前药对肿瘤细胞的杀灭效果
体外细胞培养试验:
取植有艾氏腹水癌的晚期小白鼠腹水,加入生理盐水,离心去掉上清液培养并稀释,制成每毫升含1000细胞的标准溶液。
取各组5-氟尿嘧啶及空白与上述标准溶液反应,培养,观察,记录细胞总数,反应后4h和12h时的死亡细胞数及百分率,并与24小内反复观察。详细结果见表2。
表2.各组5-氟尿嘧啶前药对肿瘤细胞的杀灭率
由表2可知,实施例1-4的5-氟尿嘧啶前体在4h时对肿瘤细胞的杀灭率分别为60%、47%、45%、40%和44%,大于氟尿嘧啶的30%,在24h时对肿瘤细胞的杀灭率分别为96%、98%、99%、100%和98%,大于氟尿嘧啶的90%,由此可知,经结构改造后的5-氟尿嘧啶前体的抗肿瘤活性较5-氟尿嘧啶更高。
综上,仅为本发明之较佳实施例,不以此限定本发明的保护范围,凡依本发明专利范围及说明书内容所作的等效变化与修饰,皆为本发明专利涵盖的范围之内。
Claims (6)
2.如权利要求1所述的氟尿嘧啶前药,其特征在于,R为氢或正丙基、异丙基、异丁基、仲丁基中的一种。
4.如权利要求1或2所述的氟尿嘧啶前药在制备用于癌症或肿瘤的药物中的应用。
5.如权利要求4所述的应用,其特征在于,所述癌症或肿瘤包括消化道癌、乳腺癌、卵巢癌、绒毛膜癌、子宫颈癌、肝癌、膀胱癌。
6.一种用于癌症或肿瘤的制剂,其特征在于,所述制剂包括权利要求1或2所述的氟尿嘧啶前药和药学上可接受的辅料。
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