WO2021023016A1 - 乐伐替尼酸的噻唑酮衍生物及其应用 - Google Patents

乐伐替尼酸的噻唑酮衍生物及其应用 Download PDF

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WO2021023016A1
WO2021023016A1 PCT/CN2020/103716 CN2020103716W WO2021023016A1 WO 2021023016 A1 WO2021023016 A1 WO 2021023016A1 CN 2020103716 W CN2020103716 W CN 2020103716W WO 2021023016 A1 WO2021023016 A1 WO 2021023016A1
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acid
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李飞
周新基
张毅
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江苏千之康生物医药科技有限公司
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  • the invention belongs to the field of pharmacy, and provides a thiazolone derivative 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline methyl of levatinib acid Acylthiazolone and its application.
  • Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activity of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4) ).
  • VEGF vascular endothelial growth factor
  • Lenvatinib also inhibits fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, platelet-derived growth factor receptor ⁇ (PDGFR ⁇ ), KIT, and RET9 (Int J Cancer. 2008, 122, 664-671).
  • Lenvatinib can cause serious side effects, including heart failure, thrombosis (arterial thromboembolic events), liver damage (hepatotoxicity), kidney damage (kidney failure and injury), perforation of the gastrointestinal tract or abnormal connections between the stomach or intestines, electrocardiogram activity Changes (prolonged QT interval), hypocalcemia, concomitant headaches, seizures and visual changes (reversible leukoencephalopathy syndrome), severe bleeding (hemorrhage), risk of unborn children if the patient is treated during pregnancy, and thyroid stimulation Injury inhibition of hormone production appears (Oncotarget.2016, 7:44545-44557).
  • lenvatinib acid a derivative of lenvatinib
  • the present invention provides a thiazolone derivative of levatinib acid and its application.
  • This class of drugs has anti-tumor cell proliferation activity similar to lenvatinib, and this activity is related to high free radicals in the tumor microenvironment. Due to the lower concentration of free radicals in normal cells, these drugs have less toxicity to normal cells. It has excellent anti-cancer effect and good safety, and can be used to prepare drugs for treating tumors.
  • the therapeutic tumor medicine, the active ingredient is the above-mentioned compound or a pharmaceutically acceptable salt thereof.
  • the anti-tumor proliferation activity of the target compound of the present invention was significantly reduced, suggesting that the target compound of the present invention has an anti-tumor proliferation activity and tumor cell Of free radicals. Due to the low concentration of free radicals in normal cells, these drugs have less toxicity to normal cells.
  • the 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolineformylthiazolone obtained in the present invention has the same properties as levatinib Similar anti-tumor cell proliferation activity, with less toxicity to normal cells. It has excellent anti-cancer effect and good safety, and can be used to prepare drugs for treating tumors.
  • Figure 1 is a synthetic route diagram of target compound 1
  • Figure 2 is a schematic diagram of the in vitro inhibitory effect of target compound 1 on the proliferation of human liver cancer HepG2 tumor cells;
  • Figure 3 is a schematic diagram of the growth inhibitory effect of target compound 1 on subcutaneously transplanted human liver cancer HepG2 cells;
  • Figure 4 shows the growth inhibitory effect of target compound 1 on subcutaneously transplanted human liver cancer HepG2 cells-a schematic diagram of the mass of the terminal tumor
  • Figure 5 is a schematic diagram showing the growth inhibitory effect of target compound 1 on human liver cancer HepG2 cell subcutaneously transplanted tumor-body weight change;
  • Example 1 Synthesis of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolineformylthiazolone (target compound), see Figure 1 ;
  • Example 2 Screening of target compound's in vitro tyrosine kinase inhibitory activity
  • Example 3 Investigation of the stability of the target compound in a normal environment
  • target compound 1 100 ⁇ moL/L 1.0mL of target compound 1 acetonitrile solution, add 250 ⁇ moL/L H 2 O 2 pH 7.4 PBS buffer solution 4.0mL, mix well, use high performance liquid chromatography to determine the peak area of target compound 1; place 0.5 at room temperature At 1 hour, the peak area of target compound 1 was measured by high performance liquid chromatography and compared with the peak area at 0 hour. Get the relative value.
  • the results show that the target compound 1 can be quickly converted into lenvatinib acid under H 2 O 2 environmental conditions.
  • Example 5 Study on the in vitro inhibitory effect of the target compound on tumor cell proliferation under the normal state and the state of removing free radicals in advance
  • Free radical removal group Take logarithmic growth phase human liver cancer HepG2 tumor cells, add 0.25% trypsin for 3 minutes, suspend the cells with 10% calf serum RPMI-1640, count, and adjust the cell concentration to 1 ⁇ 10 5 cells/ mL, inoculate 100 ⁇ L/well in a 96-well cell culture plate dedicated to Top-count, and incubate at 37°C and 5% CO 2 for 24h. Then the cells were pretreated with the free radical scavenger N-acetylcysteine (NAC, 20mmoL/L) for 1 hour, and divided into experimental group and control group. The experimental group was added with the target compound solution, each concentration was four times The volume of each well is 200 ⁇ L. The culture was continued for 72 hours. Before the end of the culture, 3 H-TdR 3 ⁇ 10 5 Bq was added to each well, and the CPM (count per minute) value of each well was measured with Top-count.
  • NAC free radical scavenger N-acety
  • Figure 2 The inhibitory effect of levatinib acid on the proliferation of human liver cancer HepG2 tumor cells in vitro is stronger than that of levatinib.
  • the compound 1 of the example of the present invention has a stronger in vitro inhibitory effect on the proliferation of human liver cancer HepG2 tumor cells in a normal state than lenvatinib, but has a smaller in vitro inhibitory effect on the proliferation of human liver cancer HepG2 tumor cells after removing free radicals in advance.
  • Example 6 The inhibitory effect of the target compound on the growth of human liver cancer HepG2 cell transplanted subcutaneously
  • Dosage regimen tumor model nude mice are divided into negative control group, positive control group (lenvatinib, 30mg/kg), low-dose group (compound 1, 15mg/kg), middle-dose group (compound 1, 30mg) /kg), high-dose group (compound 1, 60mg/kg), were administered intragastrically (1 time/day) for 2 weeks, the body mass of nude mice was measured every 3 days, and the tumor length and diameter were measured with vernier calipers. Short diameter, draw the growth curve of subcutaneous tumor. Nude mice were sacrificed by cervical dislocation 24 hours after the last administration, the subcutaneous transplanted tumor was stripped, and the mass of the terminal tumor was weighed.

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Abstract

4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰噻唑酮及其应用，结构符合通式(I) ，该类药物在正常条件下药效较弱，在高自由基环境中不稳定，能够产生具有更强药效的分子。该类药物具有良好的药效和安全性，可用于***药物的制备。

Description

乐伐替尼酸的噻唑酮衍生物及其应用 技术领域
本发明属于制药领域，提供乐伐替尼酸的噻唑酮衍生物4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰噻唑酮及其应用。
背景技术
乐伐替尼(Lenvatinib)是一种受体酪氨酸激酶(RTK)抑制剂，抑制血管内皮生长因子的激酶活性(VEGF)的受体VEGFR1(FLT1)，VEGFR2(KDR)，和VEGFR3(FLT4)。Lenvatinib也抑制成纤维细胞生长因子(FGF)受体FGFR1，2，3和4，血小板衍生生长因子受体α(PDGFRα)，KIT，和RET9(Int J Cancer.2008,122,664-671)。适用于有局部的复发或转移、进展性、放射性碘-难治性分化型甲状腺癌以及肝癌患者的治疗。Lenvatinib可以引起严重副作用，包括心衰、血栓形成(动脉血栓栓塞事件)、肝损伤(肝毒性)、肾损伤(肾衰竭及损伤)、胃肠道穿孔或胃或肠之间异常连接、心电图活动发生变化(QT间隔延长)、低血钙、伴随性头痛、癫痫发作和视觉变化(可逆性白质脑病综合征)、严重出血(大出血)、如果患者妊娠期间治疗会出现未出生儿风险及促甲状腺激素产生出现损伤性抑制(Oncotarget.2016,7:44545-44557)。
Figure PCTCN2020103716-appb-000001
申请人发现：乐伐替尼的衍生物乐伐替尼酸具有与乐伐替尼相似的抗肿瘤增殖活性，但是半衰期短，药效难以持久。
发明内容
解决的技术问题：本发明针对上述技术问题，提供乐伐替尼酸的噻唑酮衍生物及其应用。该类药物具有与乐伐替尼相似的抗肿瘤细胞增殖活性，这种活性和肿瘤微环境的高自由基有关。由于正常细胞自由基浓度较低，该类药物对正常细胞具有更小的毒性。具有优异的抗癌作用和良好的安全性，可用于制备***的药物。
技术方案：乐伐替尼酸的噻唑酮衍生物，命名为4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰噻唑酮，结构符合通式(I)
Figure PCTCN2020103716-appb-000002
上述化合物或其药学上可接受的盐在制备***药物中的应用。
***药物，有效成分为上述化合物或其药学上可接受的盐。
将肿瘤细胞先用自由基清除剂N-乙酰半胱氨酸(NAC)预处理1小时，本发明目标化合物的抗肿瘤增殖活性显著下降，提示本发明目标化合物的抗肿瘤增殖活性和肿瘤细胞中的自由基有关。由于正常细胞内自由基浓度较低，该类药物对正常细胞具有更小的毒性。
有益效果：本发明获得的4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰噻唑酮，具有与乐伐替尼相似的抗肿瘤细胞增殖活性，对正常细胞具有更小的毒性。具有优异的抗癌作用和良好的安全性，可用于制备***的药物。
附图说明
图1为目标化合物1的合成路线图；
图2为目标化合物1对人肝癌HepG2肿瘤细胞增殖体外抑制作用示意图；
图3为目标化合物1对人肝癌HepG2细胞皮下移植瘤的生长抑制作用示意图；
图4为目标化合物1对人肝癌HepG2细胞皮下移植瘤的生长抑制作用-终末瘤体质量示意图；
图5为目标化合物1对人肝癌HepG2细胞皮下移植瘤的生长抑制作用-体重变化示意图；
具体实施方式
下面的实施例可使本专业技术人员可全面的理解本发明，但不以任何方式限制本发明。
实施例1：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰噻唑酮(目标化合物)的合成，参见图1；
1.1 4-氯-7-甲氧基喹啉-6-甲酸甲酯(3)的合成
7-甲氧基-4-氧代-1，4-二氢喹啉-6-甲酸甲酯(2，参考文献方法合成：中国药物化学杂志，2015，285-288)2.56g置于50mL干燥茄形瓶中，向其中加入20mL二氯亚砜和3滴DMF，125℃下回流搅拌3h。反应结束后，旋干二氯亚砜，向其中加入100mL二氯甲烷至完全溶解，倒入至200mL的饱和碳酸氢钠溶液当中，搅拌1h至无气泡冒出。萃取，用100mL的饱和食盐水洗涤一次，收集有机相，通过快速柱层析(DCM:MeOH＝300:1至100:1)得到0.95g淡黄色固体。
1.2 4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基喹啉-6-甲酸甲酯(5)的合成
称取中间体4(0.326g,1.44mmol，参考文献方法合成：中国药物化学杂志，2015， 285-288)置于25mL干燥茄形瓶中，向其中加入10mL的DMF和无水碳酸钾(0.398g,2.88mmol)，室温搅拌10min，向其中加入中间体3(0.300g,0.959mmol)，氮气保护下，置于75℃下搅拌30h。冷却至室温，用20mL的二氯甲烷萃取两次，饱和食盐水洗涤一次，通过快速柱层析(DCM:MeOH＝80:1)得到0.217g的白色固体。
1.3 4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基喹啉-6-甲酸(6)的合成
称取中间体5(2.0g,4.53mmol)置于50mL的干燥茄形瓶中，向其中加入10mL的2N氢氧化钠溶液和10mL的甲醇溶液，置于40℃下搅拌24h至固体完全溶解。反应结束后，用2M的盐酸溶液调节pH至6–7，有大量淡黄色固体析出，抽滤，滤饼用10mL的甲醇洗涤，通过快速柱层析(DCM:MeOH＝20:1)得到1.47g白色固体。 1H NMR(DMSO-d6,400MHz)δ(ppm):8.55(s,1H),8.18(s,1H),8.15(d,J＝2.6Hz,1H),7.53(s,1H),7.34(d,J＝3.5Hz,2H),7.13(s,1H),6.46(s,1H),5.72(s,1H),3.86(s,3H),2.51(s,1H),0.61(s,2H),0.37(s,2H).
1.4 4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基喹啉-6-甲酰噻唑酮(1)的合成
在100mL茄形瓶中加入4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基喹啉-6-甲酸1.00g(2.3mmol)，二氯甲烷20mL，二环己基碳二亚胺0.531g(2.5mmol)，4-二甲氨基吡啶0.315g(2.5mmol)，室温搅拌20min后，再加入1,3-噻唑烷-2-酮0.242g(2.3mmol)，室温下继续搅拌4h，抽滤。收集滤液，加入适量水，用二氯甲烷萃取三次，合并有机相，并用无水硫酸钠干燥，快速柱层析(二氯甲烷：甲醇＝85：1)纯化，得到米黄色固体0.625g，产率53％。用乙酸乙酯、石油醚打浆得到白色晶体0.512g，产率43％。
1H NMR(400MHz,DMSO-D6)δ：8.61(d,J＝5.2Hz，1H),8.23(d,J＝9.1Hz,1H),8.14(s,1H),7.94(s,1H),7.45(d,J＝2.7Hz,1H),7.40(s,1H),7.21(dd,J＝9.1,2.7Hz,1H),7.16(d,J＝2.6Hz,1H),6.48(d,J＝5.2Hz,1H),4.22(s,2H),3.89(s,3H),3.45(s,2H),2.54(dt,J＝10.1,3.3Hz,1H),0.63(d,J＝5.2Hz,2H),0.39(s,2H).
实施例2：目标化合物体外酪氨酸激酶的抑制活性筛选
将一系列梯度浓度的受试化合物，在室温条件下与特定浓度的酶溶液共同孵育5min，之后加入适量的酶反应底物、ATP，启动酶反应过程，30min后，向酶反应体系中加入适量的反应终止液和检测液，孵育1h后，在多功能酶标仪上，测定特定化合物浓度下的酶活力，并计算不同浓度的化合物对酶活力的抑制活性，之后根据四参数方程，对不同浓度化合物下酶活力的抑制活性进行拟合，计算出IC50值。
表1目标化合物体外酪氨酸激酶的抑制活性(IC50，nM)
化合物 VEGFR2(KDR)
1 26
乐伐替尼 4
乐伐替尼酸 2
结果显示，目标化合物1的体外酪氨酸激酶的抑制活性明显低于乐伐替尼或者乐伐替尼酸。提示目标化合物1在正常条件下，具有比较小的细胞活性。
实施例3：目标化合物在正常环境中的稳定性考察
100μmoL/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。
表2目标化合物在pH 7.4的PBS缓冲溶液6小时和12小时的稳定性考察
化合物编号 6小时 13小时
1 92％ 85％
以上实验结果显示：目标化合物1在pH 7.4的PBS缓冲溶液中比较稳定，不容易被水解。
实施例4：目标化合物在H 2O 2环境中的稳定性考察
100μmoL/L的乐伐替尼酸的乙腈溶液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乐伐替尼酸的峰面积。
100μmoL/L的目标化合物1的乙腈溶液1.0mL，加入250μmoL/L H 2O 2的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3目标化合物在H 2O 2环境中的稳定性考察
化合物编号 0.5小时 1小时
1 51％ 25％
乐伐替尼酸 45％ 65％
结果显示，目标化合物1在H 2O 2环境条件下能够快速转变为乐伐替尼酸。
实施例5：目标化合物正常状态、预先去除自由基状态下对肿瘤细胞增殖体外抑制作用研究
取对数生长期人肝癌HepG2肿瘤细胞，加入0.25％胰酶消化3min，用含10％小牛血清RPMI-1640悬浮细胞，计数，调细胞浓度为1×10 5个/mL，以100μL/孔接种于Top-count专用96孔细胞培养板中，37℃，5％CO 2孵育24h。然后将细胞分为实验组和对照组，实验组加入目标化合物溶液，每一浓度均为四复孔，且每孔体积均补足200μL。各组加样后分别继续培养72h，于培养结束前，每孔分别加入 3H-TdR 3×10 5Bq，用Top-count测定各孔CPM(count per minute)值。计算各实验组药物对细胞增殖的半数抑制浓度(median inhibition concentration，IC 50)。
预先去除自由基组：取对数生长期人肝癌HepG2肿瘤细胞，加入0.25％胰酶消化3min，用含10％小牛血清RPMI-1640悬浮细胞，计数，调细胞浓度为1×10 5个/mL，以100μL/孔接种于Top-count专用96孔细胞培养板中，37℃，5％CO 2孵育24h。然后将细胞先用自由基清除剂N-乙酰半胱胺酸(NAC，20mmoL/L)预处理1小时，分为实验组和对照组，实验组加入目标化合物溶液，每一浓度均为四复孔，且每孔体积均补足200μL。分别继续培养72h，于培养结束前，每孔分别加入 3H-TdR 3×10 5Bq，用Top-count测定各孔CPM(count per minute)值。
以上实验结果显示(图2)：乐伐替尼酸对人肝癌HepG2肿瘤细胞增殖体外抑制作用 比乐伐替尼更强。本发明的实施例化合物1在正常状态对人肝癌HepG2肿瘤细胞增殖体外抑制作用比乐伐替尼更强，但是在预先去除自由基下的对人肝癌HepG2肿瘤细胞增殖体外抑制作用较小。
实施例6：目标化合物对人肝癌HepG2细胞皮下移植瘤的生长抑制作用
选用6周龄BALB/c-nu雌、雄各15只，取对数生长期的人肝癌HepG2细胞，以5×10 6个细胞·0.2mL -1·只 -1的浓度，接种于裸鼠右腋下部皮下。
给药方案:成瘤模型裸鼠被分为阴性对照组、阳性对照组(乐伐替尼，30mg/kg)，低剂量组(化合物1，15mg/kg)、中剂量组(化合物1，30mg/kg)、高剂量组(化合物1，60mg/kg)，分别经灌胃给药(1次/每天)，持续2周，每3天测定一次裸鼠体质量、用游标卡尺测量肿瘤长径及短径，绘制皮下肿瘤生长曲线。末次给药24h后颈椎脱臼法处死裸鼠，剥离皮下移植瘤，称量终末瘤体质量。
抑制效果见图3、终末瘤体质量见图4、体重变化见图5：给药后，各组均显示出显著的抑制肿瘤生长作用，高剂量组显示出更好的治疗作用。所有试验组裸小鼠体重没有明显差异，但是均小于阴性对照组。
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。

Claims (3)

  1. 4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰噻唑酮，其特征在于结构符合通式(I)
    Figure PCTCN2020103716-appb-100001
  2. 权利要求1所述化合物或其药学上可接受的盐在制备***药物中的应用。
  3. ***药物，其特征在于有效成分为权利要求1所述化合物或其药学上可接受的盐。
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CN1478078A (zh) * 2000-10-20 2004-02-25 ������������ʽ���� 含氮芳环衍生物
CN107513057A (zh) * 2017-09-06 2017-12-26 南京医科大学 一类乐伐替尼的乏氧活化前药及其应用
CN110437223A (zh) * 2019-08-06 2019-11-12 江苏千之康生物医药科技有限公司 乐伐替尼酸的噻唑酮衍生物及其应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1478078A (zh) * 2000-10-20 2004-02-25 ������������ʽ���� 含氮芳环衍生物
CN107513057A (zh) * 2017-09-06 2017-12-26 南京医科大学 一类乐伐替尼的乏氧活化前药及其应用
CN110437223A (zh) * 2019-08-06 2019-11-12 江苏千之康生物医药科技有限公司 乐伐替尼酸的噻唑酮衍生物及其应用

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