CN110698491B - 2-(喜树碱-10-氧基)乙酰胺类化合物和应用 - Google Patents
2-(喜树碱-10-氧基)乙酰胺类化合物和应用 Download PDFInfo
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- CN110698491B CN110698491B CN201911102277.4A CN201911102277A CN110698491B CN 110698491 B CN110698491 B CN 110698491B CN 201911102277 A CN201911102277 A CN 201911102277A CN 110698491 B CN110698491 B CN 110698491B
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Abstract
本发明公开的2‑(喜树碱‑10‑氧基)乙酰胺类,为具有以下通式(I)的化合物,式中,R2N为仲氨基,R′为氢、乙基,等。该类化合物的抗肿瘤活性高,毒性小。本发明还公开了通式(I)化合物的制备方法,其药物组合物和作为抗癌药物制剂的用途。
Description
技术领域
本发明属于抗癌药物制备技术领域,具体涉及一种2-(喜树碱-10-氧基)乙酰胺类化合物和应用。
背景技术
癌症是我国死亡率高的重大疾病。近30年来,我国癌症发生率正处于快速上升期,癌症发病率约为200/10万人,每年新发病例达320万例以上,死亡约270多万,在治患者达700万人以上。目前癌症的主要治疗手段仍然是手术治疗、放射治疗及药物治疗,但在很大程度上药物治疗仍然发挥着重要作用。因此,研究开发新的抗癌药物具有重要意义。
近二十年来,激酶抑制剂成为抗肿瘤药物研究的热点,并有三十多种激酶抑制剂上市。如表皮生长因子酪氨酸激酶抑制剂吉非替尼、奥希替尼,Bruton酪氨酸抑制剂依鲁替尼,BRAF抑制剂威罗菲尼等用作抗癌药物,治疗肺癌、血癌、黑色素瘤等。但是,激酶抑制剂容易产生获得性耐药、抗肿瘤谱狭窄、治疗费用昂贵。特别是经过几代激酶抑制剂的治疗后,肿瘤获得性变异更加分散,高度分散和异质化的变异成为靶向肿瘤的激酶抑制剂的不可忽视的局限性。
因此,仍然需要研发新一代的广谱抗癌化疗药物。拓扑异构酶Ι在肿瘤细胞中高度表达,喜树碱类拓扑异构酶Ι抑制剂具有广谱抗肿瘤效应。10-羟基喜树碱是从喜树中分离得到的一种生物碱,具有较强的细胞毒性,对消化道肿瘤、肝癌、膀胱癌、白血病等具有较好的疗效,但其毒性大、水溶性差,且不能口服给药。因此,继续设计、合成、评价喜树碱衍生物,发现结构新颖、高效低毒的喜树碱类抗肿瘤化疗新药仍然具有重要意义。
发明内容
为了克服上述现有技术的缺点,本发明的目的在于提供一种2-(喜树碱-10-氧基)乙酰胺类化合物和应用,该类化合物的抗肿瘤活性比10-羟基喜树碱更高,毒性小,口服有效,可应用于抗癌药物制剂的制备。
为了达到上述目的,本发明采用以下技术方案予以实现:
本发明公开了一种2-(喜树碱-10-氧基)乙酰胺类化合物,其结构式为:
其中,R2N为氨基;R′为氢或乙基;
进一步地,所述的R2N为二乙氨基、1-哌啶基、4-甲基-1-哌啶基、4-甲基-1-哌嗪基、4-二甲氨基-1-哌啶基、1-吡咯烷基等。
进一步地,所述化合物为如下化合物中的一种:
上述2-(喜树碱-10-氧基)乙酰胺类化合物经一步反应合成,具体方法如下:
在碱性试剂存在下,2-溴乙酰胺或2-氯乙酰胺与10-羟基喜树碱或10-羟基-7-乙基喜树碱(SN-38)通过亲核取代反应生成2-(喜树碱-10-氧基)乙酰胺类化合物。合成路线如下:
式中,R2N为氨基;R′为氢或乙基。M2CO3为碳酸钠、碳酸钾或碳酸铯。
本发明还公开了2-(喜树碱-10-氧基)乙酰胺类化合物在制备抗癌药物中的应用。
优选地,所述抗癌药物可用于肺癌、结肠癌等实体瘤的治疗。
优选地,本发明所述的2-(喜树碱-10-氧基)乙酰胺类化合物与其他类型的抗癌药物,如抗代谢抗癌药、EGFR抑制剂、BTK抑制剂等组成的药物复合物,获得更佳的抗癌效果。
所述抗癌药物制剂为片剂、胶囊剂或注射剂,其中每片、每粒或每支制剂中含10-100mg的2-(喜树碱-10-氧基)乙酰胺类化合物。
优选地,所述抗癌药物制剂为片剂或胶囊剂,每片片剂或每粒胶囊中含有10~50mg的2-(喜树碱-10-氧基)乙酰胺类化合物。
进一步,所述抗癌药物制剂还包括辅料,辅料包括稳定剂、增溶剂、润滑剂和崩解剂中的一种或几种。进一步优选地,辅料包括淀粉、糊精、葡萄糖、乳糖、纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮、果胶、环糊精、土温-80、聚乙烯醇、硬脂酸镁和滑石粉中的一种或多种。
与现有技术相比,本发明具有以下有益效果:
1)结构新颖,本发明涉及的化合物给10-羟基喜树碱结构中连接了乙酰胺的结构片段,结构新颖,经检索,未见文献报道。
2)抗肿瘤活性更佳,如化合物3是10-羟基喜树碱的衍生物;化合物8是SN-38的衍生物,化合物3和8的体外抗人肿瘤细胞增殖的活性分别强于10-羟基喜树碱和SN-38,也强于文献已经报道3和8的类似物,2-(喜树碱-10-氧基)乙酸乙酯和2-(喜树碱-10-氧基)乙酸。
3)毒性小,化合物SN-38给小鼠静脉给药的LD50为30mg/kg。化合物8(SN-38的衍生物)给小鼠静脉给药的LD50为70mg/kg。
因此,本发明提供的2-(喜树碱-10-氧基)乙酰胺类化合物可用于制备抗癌药物制剂,能够为癌症的临床治疗提供更多的选择。
附图说明
具体实施方式
为了使本技术领域的人员更好地理解本发明方案,下面将通过实施例对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分的实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都应当属于本发明保护的范围。
下面对本发明做进一步详细描述:
1、合成化合物1-9的具体实施例
以下通过本发明的一些代表性化合物的合成过程和药效对本发明做进一步说明。代表性化合物的编号、结构式如下:
实施例1:N,N-二乙基-2-(喜树碱-10-氧基)乙酰胺(化合物1)的合成
向50mL茄型瓶中加入10-羟基喜树碱(0.55g,1.5mmol),N,N-二甲基甲酰胺(9mL)和K2CO3(0.42g,3.0mmol),磁力搅拌下加入N,N-二乙基-2-溴乙酰胺(0.35g,1.8mmol)。混合物于室温搅拌4h,旋转蒸发除去溶剂,向残余物中加入水20mL,二氯甲烷30mL,用稀盐酸(1mol/L)调节水相至中性。转入分液漏斗,分出有机相,水相再有二氯甲烷20mL萃取一次。合并有机相,用水洗一次,无水硫酸钠干燥。过滤,旋转蒸发除去二氯甲烷,残留物用二氯甲烷和甲醇结晶,得淡黄色固体粉末0.38g,收率53.0%。1H NMR(400MHz,DMSO-d6)δ8.53(s,1H,Ar-H),8.10(d,J=9.3Hz,1H,Ar-H),7.55(d,J=8.2Hz,1H,Ar-H),7.44(s,1H,Ar-H),7.30(s,1H,Ar-H),6.52(s,1H,OH),5.43(s,2H,OCH2),5.27(s,2H,OCH2),5.01(s,2H,NCH2),3.38(d,J=10.7Hz,4H,NCH2),1.88(m,2H,CH2),1.23(d,J=6.4Hz,3H,CH3),1.07(s,3H,CH3),0.89(s,3H,CH3)ppm。
实施例2:1-(1-吡咯烷基)-2-(喜树碱-10-氧基)乙酮(化合物2)的合成
同化合物1的合成。用N-(2-溴乙酰基)吡咯烷代替N,N-二乙基-2-溴乙酰胺。1HNMR(400MHz,DMSO-d6)δ8.53(s,1H,Ar-H),8.09(d,J=9.2Hz,1H,Ar-H),7.56(dd,J=9.2,2.7Hz,1H,Ar-H),7.46(d,J=2.6Hz,1H,Ar-H),7.30(s,1H,Ar-H),6.52(s,1H,OH),5.43(s,2H,OCH2),5.27(s,2H,OCH2),4.94(s,2H,NCH2),3.62(dd,J=10.5,6.5Hz,1H,NCH2),3.56(t,J=6.7Hz,2H,NCH2),3.38(s,2H,CH2),3.15(dd,J=7.3,4.2Hz,1H,CH2),1.94(dd,J=13.6,6.8Hz,2H,CH2),1.84(m,2H,CH2),0.89(t,J=7.3Hz,3H,CH3).
实施例3:1-(1-哌啶基)-2-(喜树碱-10-氧基)乙酮(化合物3)的合成
同化合物1的合成。用N-(2-溴乙酰基)哌啶代替N,N-二乙基-2-溴乙酰胺。1H NMR(400MHz,DMSO-d6)δ8.52(s,1H,Ar-H),8.09(d,J=9.2Hz,1H,Ar-H),7.55(dd,J=9.2,2.7Hz,1H,Ar-H),7.46(d,J=2.7Hz,1H,Ar-H),7.29(s,1H,Ar-H),6.52(s,1H,OH),5.43(s,2H,OCH2),5.26(s,2H,OCH2),5.02(s,2H,NCH2),3.47(d,J=4.9Hz,4H,NCH2),1.87(m,2H,CH2),1.61(s,4H,CH2),1.47(s,2H,CH2),0.89(t,J=7.3Hz,3H,CH3)ppm。
实施例4:1-(4-甲基-1-哌嗪基)-2-(喜树碱-10-氧基)乙酮(化合物4)的合成
同化合物1的合成。用1-(2-溴乙酰基)-4-甲基哌嗪代替N,N-二乙基-2-溴乙酰胺。1HNMR(400MHz,DMSO)δ8.52(s,1H,Ar-H),8.09(d,J=9.2Hz,1H,Ar-H),7.56(dd,J=9.2,2.7Hz,1H,Ar-H),7.47(d,J=2.6Hz,1H,Ar-H),7.30(s,1H,Ar-H),6.52(s,1H,OH),5.43(s,2H,OCH2),5.27(s,2H,OCH2),5.05(s,2H,NCH2),3.54(s,4H,NCH2),2.36(s,4H,NCH2),2.29(s,3H,CH3),1.75-1.99(m,2H,CH2),0.89(t,J=7.3Hz,3H,CH3).
实施例5:1-(4-N,N-二甲基氨基-1-哌啶基)-2-(喜树碱-10-氧基)乙酮(化合物5)的合成
同化合物1的合成。用N-(2-溴乙酰基)-4-N,N-二甲基氨基哌啶代替N,N-二乙基-2-溴乙酰胺。1H NMR(400MHz,DMSO)δ8.52(s,1H,Ar-H),8.10(d,J=9.3Hz,1H,Ar-H),7.56(dd,J=9.2,2.8Hz,1H,Ar-H),7.49(d,J=2.7Hz,1H,Ar-H),7.30(s,1H,Ar-H),6.53(s,1H,OH),5.43(s,2H,OCH2),5.27(s,2H,OCH2),5.06(d,J=3.0Hz,2H,NCH2),3.17-2.99(m,2H,CH2),2.66(s,6H,CH3),2.08-1.94(m,2H,CH2),1.94-1.81(m,2H,CH2),1.75-1.60(m,1H,CH2),1.51-1.37(m,1H,CH2),1.29-1.22(m,3H,NCH2),0.89(t,J=7.3Hz,3H,CH3).
实施例6:N-甲基-N-(2-二甲基氨基)乙基-2-(喜树碱-10-氧基)乙酰胺(化合物6)的合成
同化合物1的合成。用N-甲基-N-(2-二甲基氨基)乙基-2-溴乙酰胺代替N,N-二乙基-2-溴乙酰胺。1H NMR(400MHz,DMSO)δ8.50(s,1H,Ar-H),8.10(d,J=9.2Hz,1H,Ar-H),7.57(d,J=9.3Hz,1H,Ar-H),7.51(s,1H,Ar-H),7.30(s,1H,Ar-H),6.54(s,1H,OH),5.43(s,2H,OCH2),5.28(s,2H,OCH2),5.05(s,2H,NCH2),3.71-3.58(m,2H,NCH2),3.07(s,3H,NCH3),2.93-2.91(m,2H,NCH3),2.67(s,3H,NCH3),2.14(s,3H,NCH3),1.90-1.75(m,2H,CH2),0.89(t,J=7.3Hz,3H,CH3).
实施例7:1-(1-吡咯烷基)-2-(7-乙基喜树碱-10-氧基)乙酮(化合物7)的合成
同化合物1的合成。用N-(2-溴乙酰基)吡咯烷代替N,N-二乙基-2-溴乙酰胺;用10-羟基-7-乙基喜树碱代替10-羟基喜树碱。1H NMR(400MHz,DMSO-d6)δ8.06(d,J=9.2Hz,1H,Ar-H),7.52(d,J=8.4Hz,1H,Ar-H),7.42(s,1H,Ar-H),7.25(s,1H,Ar-H),6.49(s,1H,OH),5.41(s,2H,OCH2),5.27(s,2H,OCH2),4.96(s,2H,NCH2),3.56(s,2H,NCH2),3.13(m,2H,CH2),1.92(s,2H,NCH2),1.86(d,J=7.1Hz,2H,CH2),1.84(m,2H,CH2),1.70(m,1H,CH2),1.26(s,3H,CH3),1.18(m,1H,CH2),0.86(s,3H,CH3).
实施例8:1-(1-哌啶基)-2-(7-乙基喜树碱-10-氧基)乙酮(化合物8)的合成
同化合物1的合成。用N-(2-溴乙酰基)哌啶代替N,N-二乙基-2-溴乙酰胺;用SN-38代替10-羟基喜树碱。1H NMR(400MHz,DMSO-d6)δ8.05(d,J=9.2Hz,1H,Ar-H),7.50(dd,J=9.2,2.7Hz,1H,Ar-H),7.41(d,J=2.6Hz,1H,Ar-H),7.25(s,1H,Ar-H),6.49(s,1H,OH),5.40(s,2H,CH2),5.25(s,2H,OCH2),5.05(s,2H,NCH2),3.44(m,4H,NCH2),3.12(q,J=7.3Hz,2H,CH2),1.87(m,2H,CH2),1.58(s,4H,CH2),1.42(s,2H,CH2),1.27(t,J=7.6Hz,3H,CH3),0.86(t,J=7.3Hz,3H,CH3)ppm.
实施例9:1-(1-哌啶基)-2-(7-乙基喜树碱-10-氧基)乙酮(化合物8)的合成
同实施例8。用N-(2-氯乙酰基)哌啶代替N-(2-溴乙酰基)哌啶,用碳酸铯代替碳酸钾,制备了化合物8。
实施例10:1-(4-甲基-1-哌啶基)-2-(7-乙基喜树碱-10-氧基)乙酮(化合物9)的合成
同实施例8。用N-(2-溴乙酰基)-4-甲基哌啶代替N-(2-溴乙酰基)哌啶,制备了化合物9。1H NMR(400MHz,DMSO)δ8.09(d,J=9.2Hz,1H,Ar-H),7.53(dd,J=9.2,2.7Hz,1H,Ar-H),7.43(d,J=2.7Hz,1H,Ar-H),7.27(s,1H,Ar-H),6.52(s,1H,OH),5.43(s,2H,OCH2),5.29(s,2H,OCH2),5.09(q,J=14.7Hz,2H,NCH2),4.30(s,1H,NCH2),3.91(s,1H,NCH2),3.15(d,J=7.4Hz,2H,CH2),3.07(s,1H,NCH2),2.61(s,1H,NCH2),1.86(m,2H,CH2),1.77–1.56(m,3H,CH2),1.30(t,J=7.6Hz,3H,CH3),1.16(d,J=12.3Hz,1H,CH2),0.97–0.83(m,7H,CH3,CH3,CH).
2、体外抗癌活性的验证
为了验证本发明合成的2-(喜树碱-10-氧基)乙酰胺类化合物的抗癌活性,以10-羟基喜树碱(10-HPCT)和10-羟基-7-乙基喜树碱(SN-38)为阳性对照药物,采用体外MTT比色法测定了化合物1-8对人肺癌细胞A549和人结肠癌细胞HCT11的生长抑制作用。
验证方法:将肿瘤细胞A549(或HCT116)培养在含10%小牛血清的RPMI1640培养基中,内含青霉素有100U·mL-1,链霉素100μg·mL-1,于37℃、5%CO2培养箱中传代培养。取0.3%胰酶消化贴壁的肿瘤细胞,含10%小牛血清的RPMI1640培养液配制细胞悬液,浓度为6×103个细胞/毫升。于96孔培养板内每孔接种200μL(约含1000个肿瘤细胞),37℃培养24h。给药组加入不同药物,每药设定的难度为1.0μmol·L-1,每组设3个平行孔。对照组加入与药等体积的溶剂,置于37℃、5%CO2培养箱中培养72h后弃去培养液,每孔加入20μL5mg·mL-1的MTT溶液,孵育4h后,弃去上清液,每孔加入DMSO 150μL,轻度振荡后用酶标仪在490nm下测定光密度值(OD)。
结果计算:以溶剂对照处理的肿瘤细胞为对照组,按照下式计算药物对肿瘤细胞的增殖抑制率:
据抑制率,采用线性回归法计算出不同化合物抑制A549和HCT116增殖的IC50值,见表1。
表1化合物1-9对两种人肿瘤细胞的生长抑制作用(IC50,μmol/L)
A549:人肺癌细胞;HCT116:人结肠癌细胞。
将表1的活性数据与结构比较,可见发现,当酰胺片段为疏水基团时,如化合物2、3、7、8和9的活性保持或强于阳性药10-HPCT或SN-38;当酰胺片段为亲水基团时,如化合物4、5、和6的活性消失。由此可见,连接于喜树碱10位的取代基对化合物的活性有显著影响。化合物3的体外活性强于10-HPCT;化合物8和9的活性强于SN-38。
化合物3是10-羟基喜树碱的衍生物,其体外抗肿瘤活性强于10-羟基喜树碱,也强于文献报道3的类似物2-(喜树碱-10-氧基)乙酸乙酯(A);化合物8和9是SN-38的衍生物,其体外抗人肿瘤细胞增殖的活性强于SN-38,也强于SN-38的类似物2-(7-乙基喜树碱-10-氧基)乙酸乙酯(B)。所述的几种化合物体外活性对比见表2。
表2.化合物抗增殖活性对比(IC50,μmol/L)
3、体内抗癌活性的验证
为了验证本发明提供化合物的体内抗癌活性,分别采用H22鼠源性肝癌小鼠模型、人结肠癌HCC116裸鼠移植瘤模型,腹腔注射给药或灌胃给药,考察了化合物8的体内抗癌活性。
1)H22鼠源性肝癌小鼠模型
验证方法:小鼠,雄性,体重19-22g。取出小鼠腹腔接种H22后第8天的腹水,用生理盐水以1:1比例稀释,制成H22细胞混悬液。用注射器在每只小鼠右腋窝皮下接种0.1mL。接种第5日,将小鼠随机分为3组,每组7只,分别为:
1)溶剂组(DMSO/PEG400/5%葡萄糖注射液)
2)化合物8高剂量组(3.0mg·kg-1)
3)化合物8低剂量组(1.0mg·kg-1)
将化合物8用DMSO/PEG400/5%葡萄糖注射液(体积比为1:4:5)溶解。接种后第5天(肿瘤体积约为200mm3)开始按上述给药方案腹腔注射给药,给药体积为10mL·kg-1,一日一次,共给药16次。给药前,记录小鼠体重。停药次日将小鼠处死,剥离出瘤块,剔除其他组织后称重。
结果:溶剂组肿瘤平均重量为1.34g;化合物8高剂量组(3.0mg·kg-1)和低剂量组(1.0mg·kg-1)的肿瘤平均重量分别为0.44g和0.51g。给药组与溶剂组相比,肿瘤的平均重量具有显著的统计学差异(P<0.01)。
结论:化合物8对小鼠体内H22鼠源性肝癌移植瘤的生长具有明显的抑制作用。
2)人结肠癌HCC116裸鼠移植瘤模型
a.腹腔注射给药
验证方法:Balb/c裸鼠(SPF级,4周龄,雄性,购于北京维通利华实验动物技术有限公司),由西安交通大学动物中心代为饲养。用注射器在每只裸鼠左腋窝皮下接种HCT116细胞2×106个(0.1mL)。待肿瘤体积生长到约100mm3,将裸鼠随机分为5组,每组4只,分别为:
①溶剂组(DMSO/PEG400/5%葡萄糖注射液)
②伊立替康盐酸盐组(10mg/kg)
③化合物8低剂量组(0.2mg/kg)
④化合物8中剂量组(0.5mg/kg)
⑤化合物8高剂量组(1.0mg/kg)
将化合物8用DMSO/PEG400/5%葡萄糖注射液(体积比为1:4:5)溶解。分组后第二天(d1)开始腹腔注射给药,两日一次,给药体积为5mL/kg,给药13次。每三天测量一次肿瘤的长和宽,按照肿瘤体积=瘤长×宽2÷2,计算体积。
结果参见图1,实验结果说明,当给药剂量为0.2mg/kg时,化合物8可明显抑制肿瘤的生长;化合物8在剂量为0.5mg/kg时的体内抗肿瘤效应与阳性药伊立替康盐酸盐剂量为10mg/kg时的体内抗肿瘤效应相同。
结论:化合物8腹腔注射给药,对人结肠癌HCT116的生长具有显著的抑制效应。
b.灌胃给药
验证方法:Balb/c裸鼠(SPF级,4周龄,雄性,购于北京维通利华实验动物技术有限公司),由西安交通大学动物中心代为饲养。用注射器在每只裸鼠左腋窝皮下接种HCT116细胞2×106个(0.1mL)。待肿瘤体积生长到约100mm3,将裸鼠随机分为5组,每组6只,分别为:
①溶剂组(DMSO/PEG400/5%葡萄糖注射液)
②伊立替康盐酸盐组(2.0mg/kg)
③化合物8低剂量组(0.5mg/kg)
④化合物8中剂量组(2.0mg/kg)
⑤化合物8高剂量组(8.0mg/kg)
将化合物8用DMSO/PEG400/5%葡萄糖注射液(体积比为1:4:5)溶解。分组后第二天(d0)开始灌胃给药,两日一次,给药体积为10mL/kg,给药13次。每两天测量一次肿瘤的长和宽,按照肿瘤体积=瘤长×宽2÷2,计算体积。
结果:见图2,由图2可以看出,当灌胃给药剂量为0.5mg/kg时,化合物8可明显抑制肿瘤的生长;当给药剂量为8.0mg/kg时,化合物8可完全抑制肿瘤的生长;相同剂量下化合物8的体内抗肿瘤效应强于阳性药伊立替康盐酸盐。
结论:化合物8灌胃给药有效,且对人结肠癌HCT116具有显著的体内抗肿瘤效应。
4、化合物8的急性毒性试验
药物:化合物8和SN-38。
用DMSO将化合物8溶解,用5%的葡萄糖注射液和PEG400稀释,配制成10mg/mL的样品溶液(5%的葡萄糖注射液:PEG400:DMSO=6:3:1,体积比)。同理,将DN-38配制成5mg/mL的样品溶液。
方法:小鼠静脉注射、腹腔注射或灌胃给药,给药体积均为5mL/kg。化合物8在该溶剂中最大溶解度为10mg/mL,即单次给药剂量最大可达到50mg/kg。大于该剂量时,每间隔30分钟给药一次,直至达到最终剂量。SN-38在该溶剂中最大溶解度为5mg/mL,即单次给药剂量最大可达到25mg/kg,大于该剂量时,每间隔30分钟给药一次,直至达到最终剂量。给药当天为第一天,观察时间为十天,确定最小致死量。
结果:实验结果见表3.
表3.化合物8对小鼠的最小致死量(n=6)
由表3中可知,化合物8对小鼠静脉注射最小致死量约为75mg/kg;腹腔注射最小致死量约为175mg/kg;灌胃给药最小致死量约为275mg/kg。SN-38静脉注射最小致死量约为25mg/kg;腹腔注射和灌胃给药300mg/kg组小鼠均未出现死亡现象。从表3中数据可以看出,化合物8静脉注射最小致死量比SN-38大,但腹腔注射和灌胃给药的最小致死量比SN-38小,初步认为是由于腹腔注射和灌胃给药后SN-38在小鼠体内吸收较差造成的。
结论:化合物8毒性比SN-38小,且在体内有一定的吸收。
5、化合物8的溶解度
采用HPLC法,测定了化合物8在水、缓冲液A(pH 4.5)和缓冲液B(pH 7.4)三种介质中的溶解度。结果见表4。
表4.化合物8的溶解度(μg/mL)
由表4可知,化合物8的溶解度优于阳性药SN-38,达到了药物研发对溶解度(10μg/mL)的要求。
综上所述,本发明公开的2-(喜树碱-10-氧基)乙酰胺类化合物,优选化合物8,易合成、活性高、毒性小、口服有效。化合物8或其药物组合物,可用于制备抗癌药物制剂,这些制剂可以是片剂、胶囊剂、口服液、颗粒剂或注射剂。这些制剂可按照各种制剂的常规制备工艺制成,其中有效成分的含量为10-100mg,优选的含量为10-50mg。
本发明涉及的口服制剂中可含有药用辅料,包括稳定剂、增溶剂、润滑剂等,如葡萄糖、乳糖、纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮、淀粉、果胶、环糊精、土温-80、聚乙烯醇、硬脂酸镁、滑石粉等。
以上内容仅为说明本发明的技术思想,不能以此限定本发明的保护范围,凡是按照本发明提出的技术思想,在技术方案基础上所做的任何改动,均落入本发明权利要求书的保护范围之内。
Claims (7)
3.权利要求1~2中任意一项所述的2-(喜树碱-10-氧基)乙酰胺类化合物在制备抗癌药物中的应用。
4.如权利要求3所述的应用,其特征在于,抗癌药物的剂型为片剂、胶囊剂或注射剂。
5.如权利要求4所述的应用,其特征在于,每片片剂、每粒胶囊剂或每支注射剂中含有10~50mg的2-(喜树碱-10-氧基)乙酰胺类化合物。
6.如权利要求3所述的应用,其特征在于,所述2-(喜树碱-10-氧基)乙酰胺类化合物联合抗代谢抗癌药、EGFR抑制剂或BTK抑制剂组成药物复合物。
7.如权利要求3所述的应用,其特征在于,所述的抗癌药物为抗肺癌或结肠癌的药物。
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