CN111499623B - 一类非核苷抗肿瘤药物的噻唑酮脲衍生物及其药物用途 - Google Patents
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Abstract
一类非核苷抗肿瘤药物的噻唑酮脲衍生物及其药物用途,其化学结构符合通式(I):
Description
技术领域
本发明属于制药领域,具体涉及一类非核苷抗肿瘤药物的噻唑酮脲衍生物及其药物用途。
背景技术
沙利度胺及其类似物泊马度胺(pomalidomide)、来那度胺(lenalidomide)是目前常用的免疫调节药物,尤其对多发性骨髓瘤具有较好疗效。来那度胺是目前唯一获NCCN指南优先推荐用于多发性骨髓瘤维持治疗的药物。来那度胺主要通过尿以原形的形式排泄,在健康受试者中,肾脏排泄量占药物总清除量的65%-85%。清除半衰期(t1/2)约为3-4小时。
目前,来那度胺已经被广泛用于多种恶性肿瘤疾病的治疗,然而,其本身仍存在一些缺陷,如具有一定的毒副作用,药物半衰期短等。来那度胺的主要不良反应是骨髓抑制,可引起III-IV度中性粒细胞减少、血小板下降,合用地塞米松或化疗时出现深静脉血栓和肺栓塞。因此,如果能够实现肿瘤靶向释放,能够减少其毒副作用。
由于肿瘤快速增长,肿瘤组织或者肿瘤细胞中的自由基浓度较高,因此,如果能够将抗肿瘤药物修饰为没有或者活性较小的前药,在自由基作用下,释放出活性较强的活性成分,就能够实现在保持高的抗肿瘤活性的同时,减少药物对正常细胞的毒性。本发明提供一类非核苷抗肿瘤药物的噻唑酮脲衍生物,该类药物采用脲键形式将来那度胺、泊马度胺的氨基酰化,由于脲键稳定,能够维持较高的血药浓度,延长作用时间。在自由基浓度较高的肿瘤组织或者肿瘤细胞中,能够快速释放出活性较强的来那度胺、泊马度胺,在保持高的抗肿瘤活性的同时,实现对肿瘤的靶向性,能够在更小的剂量下获得较好的药效,获得更好的治疗效果,更安全更有效。
伊布替尼(ibrutinib)、阿卡替尼(acalabrutinib)是目前常用的BTK抑制剂,采用类似方式,采用脲键形式将伊布替尼、阿卡替尼的氨基酰化,由于脲键稳定,能够维持较高的血药浓度,延长作用时间。在自由基浓度较高的肿瘤组织或者肿瘤细胞中,能够快速释放出活性较强的伊布替尼、阿卡替尼,在保持高的抗肿瘤活性的同时,实现对肿瘤的靶向性,能够在更小的剂量下获得较好的药效,获得更好的治疗效果,更安全更有效。
从实施例可见,将活性药物的氨基采用噻唑酮脲化,由于脲键稳定,能够维持较高的血药浓度,延长作用时间,同时能够实现药物对肿瘤的靶向释放。
发明内容
解决的技术问题:本发明提供一类非核苷抗肿瘤药物的噻唑酮脲衍生物及其药物用途,本发明所述的噻唑酮脲的衍生物,在肿瘤高自由基环境下能够释放出来抗肿瘤活性成分。具有优异的抗肿瘤作用和良好的安全性,可用于治疗肿瘤药物的制备。
技术方案:一类非核苷抗肿瘤药物的噻唑酮脲衍生物,其化学结构符合通式(I):
上述一类非核苷抗肿瘤药物的噻唑酮脲衍生物,其优选结构如下所示:
上述一类非核苷抗肿瘤药物的噻唑酮脲衍生物或其药学上可接受的盐在制备治疗肿瘤药物中的应用。
治疗肿瘤的药物,有效成分为上述一类非核苷抗肿瘤药物的噻唑酮脲衍生物或其药学上可接受的盐。
需要指出的是,我们的研究发现:实施例化合物在正常情况下能够稳定存在,在高自由基环境下,实施例化合物稳定性下降,迅速降解。
有益效果:本发明获得的噻唑酮脲的衍生物,具有较好的稳定性,能够维持更高的血药浓度。在高自由基条件环境下,能够快速代谢为具有抗肿瘤作用的非核苷类活性成分Ar-NH2。由于肿瘤细胞自由基浓度较高,本发明获得的噻唑酮脲的衍生物能够特异性的对肿瘤区域的肿瘤发挥抗肿瘤作用,减少对其他组织的毒副作用。在更小的剂量下获得更好的药效,获得更好的治疗效果,更安全更有效。
具体实施方式
下面的实施例可使本专业技术人员可全面地理解本发明,但不以任何方式限制本发明。
实施例1:目标化合物的合成
1.1来那度胺噻唑酮脲衍生物(化合物1)的合成
三光气(148mg,0.5mmol)溶于干燥的四氢呋喃(15.0mL)于0-5℃下,加入1,3-噻唑酮(155mg,1.5mmol),N,N-二异丙基乙胺(314mg,1.5mmol)搅拌1小时。于0-5℃下,加入来那度胺(358mg,1.5mmol),N,N-二异丙基乙胺(314mg,1.5mmol)搅拌1小时。加水50mL,乙酸乙酯提取,有机相用无水硫酸钠干燥,减压蒸除溶剂,粗产物经硅胶色谱柱纯化,得白色固体,化合物1(403mg,收率69.3%).1H-NMR(400MHz,DMSO-d6)δppm:11.05(s,1H),9.78(s,1H),7.82-7.80(dd,1H),7.51-7.48(m,2H),5.17-5.13(dd,1H),4.41-4.36(d,1H),4.34-4.29(m,4H),3.35(t,2H),2.97-2.88(m,1H),2.63-2.59(m,1H),2.36-2.25(m,1H),2.06-2.02(m,1H).
1.2泊马度胺噻唑酮脲衍生物(化合物2)的合成
参考化合物1的合成方法,以三光气、1,3-噻唑酮和pomalidomide合成。1H NMR(400MHz,DMSO-d6)11.07(s,1H),9.79(s,1H),7.89-7.85(dd,1H),7.59-7.52(m,2H),5.12-5.07(dd,1H),4.31(t,2H),3.36(t,2H),2.89-2.85(m,1H),2.61-2.53(m,2H),2.04-2.00(m,1H).
1.3伊布替尼噻唑酮脲衍生物(化合物3)的合成
参考化合物1的合成方法,以三光气、1,3-噻唑酮和伊布替尼合成。1HNMR(400MHz,DMSO-d6)7.77(s,1H),7.67(t,2H),7.44(t,2H),7.21-7.12(m,5H),6.91-6.69(m,1.5H),6.15-6.05(m,1H),5.73-5.58(m,1H),4.72-4.68(m,1H),4.57-4.55(m,0.5H),4.32(t,2H),3.72-3.68(m,0.5H),3.36(t,2H),3.24-3.16(m,1H),3.12-2.95(m,1H),2.28-2.22(m,1H),2.16-2.10(m,1H),1.92(d,1H),1.61-1.55(m,1H).
1.4阿卡替尼噻唑酮脲衍生物(化合物4)的合成
参考化合物1的合成方法,以三光气、1,3-噻唑酮和Boc-阿卡替尼合成。
三光气(74mg,0.25mmol)溶于干燥的四氢呋喃(10.0mL)于0-5℃下,加入1,3-噻唑酮(78mg,0.75mmol),N,N-二异丙基乙胺(117mg,0.75mmol)搅拌1小时。于0-5℃下,加入Boc-阿卡替尼(375mg,0.75mmol),N,N-二异丙基乙胺(117mg,0.75mmol)搅拌1小时。加水50mL,乙酸乙酯提取,有机相用无水硫酸钠干燥,减压蒸除溶剂,粗产物经硅胶色谱柱纯化,得白色固体,加入二氯甲烷(10mL)和三氟乙酸(2mL)的混合物,室温反应2小时,旋干溶剂,加水50mL,乙酸乙酯提取,有机相用无水硫酸钠干燥,减压蒸除溶剂,粗产物经硅胶色谱柱纯化,得白色固体,化合物4(230mg,收率58.0%).1H-NMR(400MHz,DMSO-d6)δppm:8.40(dd,1H),8.21(d,1H),8.17-8.14(m,2H),7.80-7.71(m,2H),7.20-7.11(m,2H),5.73-5.46(m,1H),3.82(t,1H),4.32(t,2H),3.61-3.58(m,1H),3.36(t,2H),2.36-2.25(m,2H),2.13-2.09(m,1H),2.03(s,3H),1.16(s,1H)
实施例2:目标化合物在正常环境和H2O2环境中的稳定性考察
正常环境:40μmoL/L的目标化合物1的乙腈溶液1.0mL,加入pH 7.4的PBS缓冲溶液4.0mL,混合均匀,采用高效液相色谱测定目标化合物1的峰面积;室温下放置6和12小时,采用高效液相色谱测定目标化合物1的峰面积,并与0小时的峰面积进行比较。得到相对值。
H2O2环境:100μmoL/L的目标化合物1的乙腈溶液1.0mL,加入250μmoL/L H2O2的pH7.4的PBS缓冲溶液4.0mL,混合均匀,采用高效液相色谱测定目标化合物1的峰面积;室温下放置0.5和1小时,采用高效液相色谱测定目标化合物1的峰面积,并与0小时的峰面积进行比较。得到相对值。
表1目标化合物在正常环境6小时和H2O2环境0.5小时的稳定性考察
化合物编号 | 正常环境6小时 | H<sub>2</sub>O<sub>2</sub>环境0.5小时 |
1 | 90% | 25% |
2 | 89% | 24% |
3 | 85% | 23% |
4 | 82% | 27% |
以上实验结果显示:目标化合物在pH 7.4的PBS缓冲溶液中比较稳定,不容易被水解。在H2O2环境条件下不稳定,被快速降解。
实施例3:目标化合物1对Lewis裸小鼠皮下移植瘤的生长抑制作用
取对数生长期的Lewis肺癌细胞,以5×106个细胞·0.2mL-1·只-1的浓度,接种于裸鼠背部皮下,常规饲养5天后,以移植瘤长短径计算瘤体相似体积。按肿瘤体积的大小来顺排,用随机区组设计分配方法将裸鼠分为5组。
给药方案:模型动物50只,随机被分为阴性对照组、低剂量组(化合物1,0.1mmol/kg)、高剂量组(化合物1,0.4mmol/kg)、来那度胺组(0.2mmol/kg),分别经口服给药(1次/每天),持续2周,处死裸鼠,同时测定动物体重。
表2目标化合物1对Lewis裸小鼠皮下移植瘤的生长抑制作用
给药后,各组均显示出显著的抑制肿瘤生长作用,化合物1低剂量组显示出与来那度胺组相似的治疗作用。化合物1中剂量组、高剂量组均显示出比来那度胺组更好的治疗作用。
表3目标化合物1对Lewis裸小鼠皮下移植瘤的模型动物体重的影响
给药后,所有试验组裸小鼠体重均小于阴性对照组,化合物1低剂量组体重和对照组体重没有明显差异,中剂量组体重、高剂量组体重和对照组体重有一定的减轻,提示有一定的毒性作用。高剂量组体重高于来那度胺组,说明其毒性小于来那度胺组。
实施例4:目标化合物3对DLBCL裸小鼠皮下移植瘤的生长抑制作用
取对数生长期的DLBCL癌细胞,以5×106个细胞·0.2mL-1·只-1的浓度,按照HBL-1:MSC以4:1的比例混合,接种于裸鼠背部皮下,常规饲养5天后,以移植瘤长短径计算瘤体相似体积。按肿瘤体积的大小来顺排,用随机区组设计分配方法将裸鼠分为5组。
给药方案:模型动物50只,随机被分为阴性对照组、低剂量组(化合物3,0.1mmol/kg)、高剂量组(化合物3,0.4mmol/kg)、伊布替尼组(0.2mmol/kg),分别经口服给药(1次/每天),持续4周,处死裸鼠,同时测定动物体重。
表4目标化合物3对DLBC裸小鼠皮下移植瘤的生长抑制作用
给药后,各组均显示出显著的抑制肿瘤生长作用,化合物3中剂量组、高剂量组均显示出比伊布替尼组更好的治疗作用。
表5目标化合物3对DLBC裸小鼠皮下移植瘤的模型动物体重的影响
给药后,所有试验组裸小鼠体重均小于阴性对照组,化合物3低剂量组体重、中剂量组体重、高剂量组体重和对照组体重有一定的减轻,提示有一定的毒性作用,但是均高于伊布替尼组,说明其毒性小于伊布替尼组。
以上实例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人是能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所做的等效变换或修饰,都应涵盖在本发明的保护范围之内。
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