CN115677812A - 一类雷公藤红素衍生物及其制备方法与应用 - Google Patents
一类雷公藤红素衍生物及其制备方法与应用 Download PDFInfo
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Abstract
Description
技术领域
本发明属于医药技术领域,具体涉及具有抑制肿瘤细胞活性的雷公藤红素衍生物及其药学上可接受的盐,该类衍生物的制备方法,以该衍生物为活性成分的药物组合物,及其在制备用于治疗和/或预防各种癌症的药物中的用途。
背景技术
恶性肿瘤依然是威胁人类健康的重大疾病。目前,肿瘤治疗的常规方法包括手术、化疗、放疗、靶向治疗和免疫治疗等。随着早期筛选、诊断、治疗和一些新型治疗手段的出现,恶性肿瘤患者的5 年生存率得到了大幅提高,但是肿瘤的复发、转移和耐药问题并未得到解决,仍有患者会因此导致最终治疗失败,这是肿瘤死亡率高的重要原因。研究证实,这些现象的产生与肿瘤干细胞(cancer stem cells,CSCs)的存在有着密切关系。CSCs最早在白血病细胞中发现,之后在多种实体瘤中也证明其存在,包括卵巢癌、乳腺癌、结肠癌、脑癌、肝癌和前列腺癌等。CSCs是指在恶性肿瘤中一小群具有干细胞特性的肿瘤细胞,具有多向分化潜能、自我更新能力及强成瘤能力,所占比例不足1%,却与肿瘤的发生、发展、侵袭、复发、转移及耐药等关系密切。
目前已开发一些靶向CSCs的小分子药物,包括天然产物及其衍生物也是抗CSCs药物的重要来源。首个进入III期临床的靶向CSCs的天然药物Napabucasin(BBI608)是来源于紫花风铃木树皮的活性化合物,为STAT3小分子抑制剂,适用于治疗转移性直肠癌、胰腺癌和胃癌等。还有一些处于临床前研究的天然产物及其衍生物,也表现出了抑制CSCs活性的潜力,包括了姜黄素(curcumin)、表没食子儿茶素(EGCG)、萝卜硫素(Sulforaphane)、白藜芦醇(resveratrol)和染料木素(genistein) 等。
雷公藤红素(Celastrol),又称为南蛇藤素,是一种来源于传统中药卫矛科植物雷公藤(Tripterygium wilfordii Hook f)的醌甲基型五环三萜类化合物。雷公藤红素具有抗炎,抗病毒,免疫调节,抗肿瘤等多种药理活性,其中抗肿瘤作用明显。雷公藤红素对肺癌,卵巢癌,肝癌,胃癌,白血病,结肠癌,乳腺癌等多种癌细胞具有抑制作用。雷公藤红素发挥抗癌活性的作用机制主要包括诱导细胞凋亡,抑制细胞增殖,抑制迁移、侵袭,抑制血管生成等。研究表明,雷公藤红素对具有干性特征的肿瘤细胞,也就是肿瘤干细胞样细胞具有一定的抑制活性,可作为靶向肿瘤干细胞药物的先导化合物。
本发明人设计并合成了一系列雷公藤红素衍生物,经细胞水平活性评价,所合成的化合物具有较好的抗肿瘤细胞增殖活性,能够明显增加肿瘤细胞中活性氧水平,可能具有一定的抗肿瘤干细胞作用,有可能应用于复发性肿瘤的治疗。
发明内容
发明目的:本发明的目的是提供一种雷公藤红素衍生物及其制备方法,以及其在抗肿瘤方面的应用。
技术方案:为了实现上述目的,根据本发明的一个方面,提供了一种如通式I所示的雷公藤红素衍生物或其药学上可接受的盐:
其中,R1代表:H,芳基,C1~C6的烷基,=O(S),氰基,羧基;R2代表:H,芳基,C1~C6的烷基,烷基或芳基取代的酰基。
进一步地,R1代表H,=O;R2代表H,芳基,C1~C6的烷基,烷基或芳基取代的酰基。
进一步地,R1代表H,=O;R2代表H,苯基,C1~C4的直链或支链的烷基,乙酰基,苯酰基。
进一步地,本发明的通式I所示的化合物或其药学上可接受的盐选自以下任意一种化合物或其药学上可接受的盐:
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-甲基哌嗪 (I-1),
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-乙基哌嗪 (I-2),
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-异丙基哌嗪(I-3),
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-苯基哌嗪 (I-4),
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-乙酰基哌嗪(I-5),
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-苯甲酰基哌嗪(I-6),
4-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-1-甲基哌嗪 -2-酮(I-7)。
根据另一个方面,本发明提供了上述由通式I表示的化合物的制备方法,
其中,R1和R2的定义如上所述,
所述方法包括如下步骤:
步骤1:雷公藤红素经硼氢化钠还原后,与乙酸酐发生反应生成式2所示化合物;
步骤2:式2所示化合物与哌嗪衍生物在HATU、DIPEA存在下发生缩合反应生成通式I所示化合物。
所述的药物组合物,所述雷公藤红素衍生物添加一种或多种药学上可接受的辅料制成制剂,包括片剂、胶囊剂、颗粒剂、液体制剂。在这些不同制剂中,本发明化合物的含量可以使0.1%~99.9%。本发明化合物的给药量可以使0.001-10000mg/kg/0.3天,根据临床需要可以适度调整。
根据还一个方面,本发明提供了上述通式I所表示的化合物或其药学上可接受的盐,在制备抗肿瘤药物中的用途,尤其是肿瘤复发与转移的药物中的用途。本发明化合物可以单独或与临床上常用的抗肿瘤药物联合应用,另外还可以与放射治疗联合应用。
有益效果:本发明合成了一类雷公藤红素衍生物,所采用的制备方法反应条件温和、原料易得、后处理方便。体外细胞水平活性评价试验表明,本发明公开的化合物具有较好的抗肿瘤细胞增殖活性,能够明显增加肿瘤细胞中活性氧水平,可能具有一定的抗肿瘤干细胞作用,因此,在抗肿瘤方面,有较好的应用前景。
附图说明
图1位合成的雷公藤红素衍生物对SKOV3细胞活性氧的影响。
具体实施方式
以下结合实施例进一步说明本发明,所举之例不应视为对本发明保护范围的限制。实施例中未注明具体条件的实验方法,通常按照常规条件以及手册中所述的条件,或按照制造厂商所建议的条件;所用的设备、材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1:中间体2的制备
称取雷公藤红素(0.225g,0.5mmol)溶于甲醇,少量分批加入NaBH4,有大量气泡产生,溶液由红色变为无色,室温下搅拌15min,2mol/L盐酸调节pH为酸性,析出大量白色固体,用乙酸乙酯萃取3次,合并有机相,有机相用饱和NaCl溶液洗涤3次,无水硫酸钠干燥,减压浓缩,得淡黄色固体Im-1。将Im-1溶于THF,加入DMAP(0.305g,2.5mmol),N2保护,室温搅拌溶解,再加入Ac2O(236ul,2.5mmol),溶液由黄色变为无色,室温反应4h,减压除去THF,用乙酸乙酯萃取3次,合并有机相,有机相用饱和NaCl溶液洗涤3次,无水硫酸钠干燥,减压浓缩,得淡黄色油状物。经硅胶柱层析分离(环己烷∶丙酮=10∶1)得到白色固体Im-2,收率70%。mp 212-213℃;1H NMR (500MHz,CDCl3)δ6.99(s,1H),5.73(dd,J=6.3,2.2Hz,1H),3.32(dd,J=20.9,6.1Hz,1H),3.09- 2.99(m,1H),2.39(d,J=15.8Hz,1H),2.30(s,3H),2.27(s,3H),2.10(d,J=14.3Hz,1H),2.06(s,3H), 2.03-1.99(m,2H),1.86-1.46(m,7H),1.40(d,J=17.7Hz,1H),1.33(s,3H),1.26(s,2H),1.21(s,3H), 1.13(s,3H),1.05(s,3H),0.89(d,J=11.4Hz,1H),0.68(s,3H);13C NMR(126MHz,CDCl3)δ184.09, 168.64,168.32,149.33,147.49,140.56,138.02,131.47,127.75,116.96,116.53,44.18,43.72,40.20,37.48, 37.18,36.68,34.56,34.36,34.11,32.64,31.53,30.52,30.46,30.06,29.48,28.83,28.09,22.90,20.67,20.40, 18.68,12.56;HRMS(ESI):m/z calcd for C33H45O6[M+H]+537.3216,found 537.3216.
实施例2:I-1的制备
称取0.1g(0.186mmol)Cel-2,加入5ml DMF溶解,加入0.106g(0.279mmol)HATU、62ul (0.372mmol)DIPEA,室温搅拌1h,然后加入0.09315g(0.93mmol)的N-甲基哌嗪,室温搅拌反应12h,蒸干溶剂,用乙酸乙酯萃取3次,合并有机相,有机相用饱和NaCl溶液洗涤3次,无水硫酸钠干燥,蒸干溶剂,得黄色油状物。制备薄层色谱(石油醚∶乙酸乙酯=2∶1)分离得到目标化合物,收率为65%。mp 224-225℃;1H NMR(500MHz,CDCl3)δ6.96(s,1H),5.74(dd,J=6.2,2.1Hz,1H), 4.30-3.54(m,4H),3.32(dd,J=20.9,6.1Hz,1H),3.05(dd,J=20.7,1.9Hz,1H),2.54-2.34(m,5H), 2.32(s,3H),2.30(s,3H),2.28(s,3H),2.09(dd,J=14.0,3.8Hz,1H),2.06(s,3H),2.04-1.99(m,2H), 1.86-1.50(m,9H),1.46(d,J=22.8Hz,1H),1.33(s,3H),1.26(s,3H),1.24(s,3H),1.11(s,3H),0.94(dt, J=14.1,3.6Hz,1H),0.62(s,3H);13C NMR(126MHz,CDCl3)δ175.93,168.58,168.37,149.29,147.28, 140.55,138.07,131.61,127.87,117.28,116.41,54.73(2C),45.84(2C),44.81,43.52,40.22,37.80,37.15, 36.66,36.00,34.25,34.20,33.98,31.85,30.97,30.90,30.82,29.98(2C),29.12,28.07,23.59,20.64,20.38, 18.59,12.54;HRMS(ESI):m/z calcd for C38H55N2O5[M+H]+619.4111,found 619.4116.
实施例3:化合物I-2的制备
参照实施例1和实施例2的合成方法,将N-甲基哌嗪换成N-乙基哌嗪。
Yield 65%;mp 207-208℃;1H NMR(500MHz,CDCl3)δ6.96(s,1H),5.74(dd,J=6.2,2.1Hz,1H),4.10-3.41(m,4H),3.31(dd,J=20.9,6.1Hz,1H),3.05(dd,J=20.9,2.0Hz,1H),2.81-2.40(m, 6H),2.36(d,J=15.8Hz,1H),2.30(s,3H),2.28(s,3H),2.10(dd,J=14.0,3.8Hz,1H),2.05(s,3H),2.04 -1.97(m,2H),1.85-1.49(m,9H),1.49-1.43(m,1H),1.33(s,3H),1.26(s,3H),1.23(s,3H),1.12(t, J=6.5,7.1Hz,6H),0.94(dt,J=14.0,3.5Hz,1H),0.62(s,3H);13C NMR(126MHz,CDCl3)δ175.69, 168.48,168.27,149.21,147.21,140.46,137.99,131.54,127.78,117.16,116.33,52.42(2C),52.14(2C), 44.77,43.45,40.09,37.70,37.05,36.60,35.85,34.21,34.17,33.88,31.77,30.89,30.86,30.71,29.91(2C), 28.99,27.99,23.43,20.55,20.30,18.46,12.47,11.59;HRMS(ESI):m/z calcd for C39H57N2O5[M+H]+ 633.4267,found 633.4270.
实施例4:化合物I-3的制备
参照实施例1和实施例2的合成方法,将N-甲基哌嗪换成N-异丙基哌嗪。
Yield 68%;mp 230-232℃;1H NMR(500MHz,CDCl3)δ6.95(s,1H),5.74(d,J=6.0Hz,1H), 4.06-3.41(m,4H),3.31(dd,J=20.9,6.2Hz,1H),3.05(d,J=20.9Hz,1H),2.71(t,J=6.5Hz,1H), 2.55-2.33(m,5H),2.30(s,3H),2.27(s,3H),2.11(d,J=17.1Hz,1H),2.05(s,3H),2.01(d,J=5.2Hz, 2H),1.84-1.48(m,9H),1.45(d,J=14.3Hz,1H),1.32(s,3H),1.25(s,3H),1.22(s,3H),1.10(s,3H), 1.08-0.98(m,6H),0.93(d,J=14.2Hz,1H),0.64(s,3H);13C NMR(126MHz,CDCl3)δ175.68,168.53,168.33,149.29,147.32,140.52,138.06,131.67,127.87,117.21,116.33,54.47(2C),48.33(2C), 44.86,43.55,40.10,37.79,37.12,36.68,35.85,34.31(2C),33.94,31.81,30.98,30.87,30.80,30.00(2C), 29.02,28.05,23.45,20.59,20.36,18.45,18.29,18.07,12.54;HRMS(ESI):m/zcalcd for C40H59N2O5 [M+H]+647.4060,found 647.4072.
实施例5:化合物I-4的制备
参照实施例1和实施例2的合成方法,将N-甲基哌嗪换成N-苯基哌嗪。
Yield 60%;mp 238-240℃;1H NMR(500MHz,DMSO)δ7.27-7.17(m,2H),6.93(d,J=8.1 Hz,2H),6.91(s,1H),6.81(t,J=7.2Hz,1H),5.76(dd,J=6.4,2.2Hz,1H),3.94-2.88(m,10H),2.41(d, J=15.8Hz,1H),2.28(s,3H),2.20(s,3H),2.11-2.00(m,2H),1.99(s,3H),1.88-1.45(m,9H),1.42 -1.36(m,1H),1.27(s,3H),1.23(s,3H),1.20(s,3H),1.09(s,3H),0.87-0.76(m,2H),0.53(s,3H);13C NMR(126MHz,CDCl3)δ176.17,168.62,168.37,149.94,149.15,147.27,140.59,138.11,131.57,129.34 (2C),127.94,117.34,116.87(2C),116.47,44.80(4C),43.53,40.27,37.89,37.23,36.68,36.07,34.25,34.17, 34.11,31.88,31.14,30.95,30.88,30.02(2C),29.21,28.12,23.67,20.65,20.39,18.70,12.55;HRMS(ESI): m/z calcd for C43H57N2O5[M+H]+681.4267,found 681.4285.
实施例6:化合物I-5的制备
参照实施例1和实施例2的合成方法,将N-甲基哌嗪换成N-乙酰基哌嗪。
Yield 68%;mp 171-173℃;1H NMR(500MHz,CDCl3)δ6.99(s,1H),5.74(dd,J=6.2,2.1Hz, 1H),4.11-3.18(m,9H),3.06(dd,J=21.0,2.0Hz,1H),2.34(d,J=14.7Hz,2H),2.30(s,3H),2.27(s,3H),2.13(s,3H),2.08(t,J=3.1Hz,1H),2.06(s,3H),1.96(dt,J=15.1,7.5Hz,1H),1.83-1.53(m,9H), 1.46(ddd,J=14.5,5.8,2.3Hz,1H),1.36(s,3H),1.27(s,3H),1,24(s,3H),1.12(s,3H),0.96(dd,J=14.1, 3.5Hz,1H),0.59(s,3H);13C NMR(126MHz,CDCl3)δ176.35,169.34,168.72,168.46,148.79,147.28, 140.55,138.07,131.43,127.90,117.25,116.71,46.01(2C),44.96(2C),43.52,41.10,40.44,37.85,37.22, 36.68,35.90,34.40,34.30,31.87,31.25,31.01,30.85,29.97(2C),29.03,28.08,23.25,21.30,20.67,20.38, 18.60,12.51;HRMS(ESI):m/z calcd for C39H55N2O6[M+H]+647.4060,found 647.4072.
实施例7:化合物I-6的制备
参照实施例1和实施例2的合成方法,将N-甲基哌嗪换成N-苯甲酰基哌嗪。
Yield 65%;mp 249-250℃;1H NMR(500MHz,DMSO)δ7.47-7.38(m,5H),7.06(s,1H), 5.75(dd,J=6.4,2.3Hz,1H),4.21-3.00(m,10H),2.37-2.31(m,1H),2.30(s,3H),2.23(s,3H),2.14(t, J=14.7Hz,2H),2.00(s,3H),1.98-1.91(m,1H),1.89-1.48(m,9H),1.39(d,J=14.3Hz,1H),1.29(s, 3H),1.21(s,6H),1.08(s,3H),0.83(d,J=13.9Hz,1H),0.52(s,3H);13C NMR(126MHz,CDCl3)δ 176.34,170.70,168.79,168.54,148.77,147.33,140.60,138.10,135.13,131.49,130.00,128.64(2C), 127.97,127.16(2C),117.29,116.79,44.95(4C),43.54,40.51,37.90,37.27,36.71,36.01(2C),34.47,34.40, 31.93,31.31,31.03,30.94,29.99(2C),29.09,28.14,23.41,20.72,20.46,18.67,12.57;HRMS(ESI):m/z calcd for C44H56N2O6[M+H]+709.4217,found 709.4232.
实施例8:化合物I-7的制备
参照实施例1和实施例2的合成方法,将N-甲基哌嗪换成4-甲基-2-氧代哌嗪。
Yield 60%;mp 244-245℃;1H NMR(500MHz,CDCl3)δ6.95(s,1H),5.74(dd,J=6.2,2.2Hz, 1H),4.45(d,J=17.4Hz,1H),4.25-4.18(m,1H),3.95-3.91(m,1H),3.68-3.58(m,1H),3.35- 3.29(m,1H),3.28-3.16(m,2H),3.06(dd,J=21.0,2.0Hz,1H),2.93(s,3H),2.35(d,J=16.1Hz,1H), 2.30(s,3H),2.25(s,3H),2.13-2.09(m,1H),2.06(s,3H),1.90-1.43(m,12H),1.34(s,3H),1.24(s, 3H),1.23(s,3H),1.11(s,3H),0.97(d,J=17.5Hz,1H),0.58(s,3H);13C NMR(126MHz,CDCl3)δ 175.64,168.65,168.41,164.95,148.83,147.37,140.58,138.07,131.51,127.94,117.24,116.59,47.49, 44.94(2C),43.46,40.57,37.76,37.18,36.65,35.82,34.39,34.27,34.19,31.87,31.20,31.10,30.67,30.51, 29.97,29.57,29.02,28.07,23.17,20.62,20.37,18.88,12.53;HRMS(ESI):m/zcalcd for C38H53N2O6 [M+H]+633.3904,found 633.3921.
实施例9
本发明的雷公藤红素衍生物对肿瘤细胞的生长抑制作用
应用MTT法检测卵巢癌细胞SKOV3、OVCAR3、A2780和正常卵巢上皮细胞IOSE80的生长抑制作用。将2×103个细胞接种于96孔板中,并让其贴壁、生长48h后,加入各浓度受试药。培养后,每孔加入50μL MTT溶液(2mg/mL),继续孵育4h后,甩板去除培养液,加入DMSO,于570nm 下测其吸光度。通过加药组与空白对照组的吸光度比值(%)求得受试药所致的细胞生长抑制率,计算IG50,结果见表1。
表1.化合物对肿瘤细胞的生长抑制活性
由表1可知,本发明中大部分化合物对卵巢癌细胞SKOV3、OVCAR3和A2780具有较好的抗增殖活性,对正常卵巢上皮细胞的毒性较雷公藤红素下降,具有一定的选择性。
实施例10
本发明的雷公藤红素衍生物卵巢癌细胞活性氧的作用
流式细胞仪检测ROS的变化:SKOV3细胞以2×105接种于6孔板培养24小时,之后加入不同浓度的目标化合物处理24小时。离心收集细胞,按照1∶1000用基础培养基稀释DCHF-DA至10μmol/L,向细胞中加入1ml稀释后的DCHH-DA。充分混匀,在细胞培养箱中孵育20分钟,每隔5min中混匀 1次。之后用基础培养基洗涤3次,以除去未进入细胞中的探针,最后置于流式管中用于流式细胞仪检测。结果见图1。
活性氧(ROS)的浓度在不同分化的肿瘤细胞中存在差异,一般癌细胞中ROS水平是增加的,而肿瘤干细胞中ROS则表现出较低的水平。通过提高肿瘤干细胞中ROS浓度,可以选择性杀死肿瘤干细胞或者是增加肿瘤干细胞对放疗和化疗的有效性。本发明合成的雷公藤红素衍生物可以增加卵巢癌细胞的ROS水平,具有抑制肿瘤干细胞的潜力,有望成为有效的抗肿瘤候选药物。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
2.根据权利要求1所述的通式I所示化合物或其药学上可接受的盐,其特征在于,R1为H或=O;R2为H,芳基,C1~C6的烷基,烷基或芳基取代的酰基。
3.根据权利要求1所述的通式I所示化合物或其药学上可接受的盐,其特征在于,R1为H,=O;R2为H,苯基,C1~C4的直链或支链的烷基,乙酰基或苯酰基。
4.化合物或其药学上可接受的盐,选自:
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-甲基哌嗪(I-1)
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-乙基哌嗪(I-2)
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-异丙基哌嗪(I-3)
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-苯基哌嗪(I-4)
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-乙酰基哌嗪(I-5)
N-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-4-苯甲酰基哌嗪(I-6)
4-(2,3-二乙酰氧基-9β,13α-二甲基-24,25,26-三去甲齐墩果烷-1,3,5(10),7-四烯-29-酰基)-1-甲基哌嗪-2-酮(I-7)。
5.一种药物组合物,其特征在于包含权利要求1所述的通式I所示化合物或其药学上可接受的盐和药学上可接受的辅料,所述药学上可接受的辅料是指药学领域的稀释剂、辅助剂和/或载体。
6.根据权利要求1所述的通式I所示化合物或其药学上可接受的盐在制备用于抑制肿瘤细胞生长的药物或抑制肿瘤干细胞药物中的应用。
7.根据权利要求1所述的通式I所示化合物或其药学上可接受的盐在制备抗肿瘤药物中的应用。
8.根据权利要求6-7中任一权利要求所述的化合物的应用,其特征在于,所述化合物或其药学上可接受的盐在制备治疗卵巢癌、乳腺癌、前列腺癌、肺癌、直肠癌、胃癌、膀胱癌、子宫癌或胰腺癌的药物的应用。
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