CN116283997A - 氘代hgfr抑制剂药物及用途 - Google Patents
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Abstract
本发明公开了氘代HGFR抑制剂，如下式Ⅰ所示，本发明涉及氘代HGFR抑制剂、其药物组合物及用途，本发明所述的一类氘代HGFR抑制剂药物，能够进一步改善HGFR抑制剂的药代动力学性质，降低给药剂量和可能的毒副作用。
Description
技术领域
本发明属于生物医药领域，具体涉及氘代HGFR抑制剂药物及用途。
背景技术
肺癌作为发病率和死亡率最高的癌症，死亡率占癌症总发病人数的18％，每年新增的肺癌患者中，非小细胞肺癌(non-small cell lung cancer,NSCLC)的患者比例高达85％。NSCLC的形成和多种癌症相关基因突变有关，Met突变是NSCLC形成的一大重要驱动基因。肝细胞生长因子受体(HGF)是Met受体唯一已知的配体，可诱导Met二聚化并进入激活状态，从而引起细胞生长和迁移相关作用，同时Met信号失调会导致下游多种信号通路的异常激活，包括RAS/MAPK通路，PI3K/Akt通路等，导致癌症的发生和恶化。抑制HGF结合，从而抑制Met介导的下游信号蛋白磷酸化，可以阻断Met依赖性癌细胞的增殖和存活。
氘代药物，既将药物分子的一个或多个碳氢键用碳氘键替代的新药物分子，可以通过改善原有药物的药代动力学性质，进而克服药物原有的易于代谢、副作用较大等缺陷。
本发明为氘代HGFR抑制剂药物，可以进一步改善目前HGFR抑制剂药物的药代动力学性质，降低给药剂量和可能的毒副作用。
发明内容
本发明提供了氘代HGFR抑制剂的氘代化合物及其药学上可接受的盐，可以进一步改善KRAS抑制剂的氘代化合物及其药学上可接受的盐的药代动力学性质，降低给药剂量和可能的毒副作用。
为了实现上述目的，如本发明所述一种如下式Ⅰ所示的HGFR抑制剂的氘代化合物及其药学上可接受的盐：
本发明所述的HGFR抑制剂的氘代化合物及其药学上可接受的盐，包括以下结构：
本发明所述HGFR抑制剂的氘代化合物及其药学上可接受的盐，其药学上可接受的盐选自甲磺酸盐、马来酸盐、盐酸盐或磷酸盐。
本发明所述的氘代化合物及其药学上可接受的盐，包括其在制备抗肿瘤药物中的应用的应用。
本发明所述的氘代化合物及其药学上可接受的盐，包括氘代化合物及其药学上可接受的盐作为活性成分和药学上可接受的载体组成。
本发明所述的氘代化合物及其药学上可接受盐的药物组合物，所述药物组合物选自胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。有益效果：与现有技术相比，本发明具有如下优点：
本发明提供一类氘代HGFR抑制剂药物，进一步改善HGFR抑制剂的药代动力学性质，降低给药剂量和可能的毒副作用。
具体实施方式
以下结合实施例对本发明作进一步说明。
实施例1
合成方法
中间体1可以参照专利CN103122000A(实施例44)的方法可制得；
中间体2的合成
向0.424g中间体1(1.0mmol)的N,N-二甲基甲酰胺(20mL)溶液中加入氢氧化钾(4mmol，4eq)和碘单质(2mmol，2eq)，室温反应3小时，TLC监测反应完全，加入亚硫酸钠饱和溶液淬灭反应，水相用乙酸乙酯(10mL*2)萃取，水(20mL*2)洗，饱和食盐(20mL)水洗无水硫酸钠干燥，浓缩柱层析，得0.41g中间体2，收率61％。
实施例1化合物的合成：
向0.34g中间体2(0.5mmol)的氘代醋酸溶液(8mL)中加入醋酸钠(1mmol，2eq)，2小时滴完，室温反应24小时，TLC检测反应完全，减压浓缩，柱层析得实施例1化合物0.17g，收率79％。1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.45(s,1H),8.38(d,J＝5.7Hz,1H),7.89(s,2H),7.83(d,J＝3.7Hz,1H),7.50(d,J＝3.7Hz,1H),3.82–3.80(m,4H),1.07–1.01(m,4H).
实施例2
中间体3，6参照专利CN103122000A(实施例44的合成路线)可制得。
中间体4，5合成参考参考实施例1的合成方法可制得。
实施例2化合物的合成：
将0.222g中间体5(1.0mmol，1eq)和0.257g中间体6(1.0mmol，1eq)、甲磺酸(1.2mmol，1.2eq)用1-甲氧基-2-丙醇溶解，90℃加热搅拌反应。16小时后，TLC监测反应完全，浓缩旋干溶剂后，经HPLC纯化，可制得实施例2化合物0.296g，收率70％。1H NMR(300MHz,Chloroform-d)δ8.94(s,1H),7.99(s,1H),7.88(s,1H),7.74(s,2H),7.43(s,1H),3.85–3.72(m,4H),1.25(dd,J＝8.8,5.5Hz,2H),1.13(dd,J＝9.0,5.7Hz,2H).
实施例3
参考实施例2化合物的合成方法，可制得实施例3化合物，收率69％。1H NMR(300MHz,Chloroform-d)δ8.96(s,1H),7.93(s,1H),7.78(s,2H),7.50(s,1H),7.46(s,1H),3.84–3.72(m,4H),1.22(dd,J＝8.9,5.6Hz,2H),1.15(dd,J＝9.0,5.7Hz,2H).
试验例1：c-Met激酶抑制活性测试
(一)试剂及耗材
| 试剂名称 | 供货商 | 货号 |
| c-Met激酶 | Cisbio | 63ADK000CB16PEG |
| 384-well plate | Perkin Elmer | 6007290 |
(二)仪器
离心机(生产厂家：Eppendorf，型号：5430)
酶标仪(生产厂家：Perkin Elmer，型号：EnVision)
(三)实验方法
将受试实施例1-3化合物和Bozitinib(伯瑞替尼)分别用DMSO配制，按比例稀释加入384孔中，将c-Met激酶(终浓度12.5nM)与化合物(DMSO终浓度为0.5％)在30℃预孵20分钟，预孵完毕后加入ATP(终浓度2.5μM)与反应底物(终浓度50μM),30℃反应1小时,1000rpm离心30秒，震荡均匀后室温孵育2小时。用酶标仪读数，Em665/620。
| Compound | c-Met IC50(nM) |
| 实施例1 | 22 |
| 实施例2 | 35 |
| 实施例3 | 20 |
| bozitinib | 37 |
实施例化合物具备优异的c-Met抑制活性，相对于阳性药bozitinib，实施例化合物活性相当，部分化合物如实施例3活性明显优于阳性药。
试验例2：化合物的药代动力学实验
(一)实验仪器和材料
高速冷冻离心机,涡旋振荡器(Vortex Genius3),高速离心机(Eppendorf5415D),一次性使用注射器,移液枪(Eppendorf),实验所用SD雄性大鼠均购自扬州大学,EDTA-K2真空采血管,生理盐水。所有口服组大鼠在给药前禁食12h,自由饮水,给药期间自由进水和进食。
(二)实验步骤
实施例1或bozitinib使用DMSO/solutol/water(10/10/80)溶解制成澄清溶液，灌胃给药化合物剂量25mg/kg，尾静脉给药化合物的剂量为5mg/kg。于尾静脉给药后的2min,10min,30min,1h,2h,3h,5h,8h,12h,16h,24h，从眼底静脉丛连续取血0.5mL至肝素管中，灌胃给药后的5min,15min,30min,1h,2h,3h,5h,8h,12h,16h,24h，从眼底静脉丛连续取血0.5mL肝素管中。将样品在8000r，4℃条件下离心10min后，取上层血浆0.15mL，-20℃条件下保存，之后进行LC-MS/MS分析。数据通过WinNolin非房室模型分析，得到关键药代动力学参数。
(三)实验结果
表1药代动力学参数
相对于阳性药bozitinib，实施例1口服给药的半衰期和达峰浓度提高明显，口服生物利用度也明显提升，可以有效改进bozitinib的给药剂量，从而降低bozitinib高剂量给药的毒副作用。
最后有必要说明的是，以上对本发明的具体实施例进行了详细描述，但其只作为范例，本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言，任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。
Claims (6)
1.一种式Ⅰ所示HGFR抑制剂的氘代化合物及其药学上可接受的盐，
其中，R1，R2独立地选自氢或者氘，且R1，R2不同为氢。
2.根据权利要求1所述的氘代化合物及其药学上可接受的盐，其特征在于，所述化合物选自以下结构：
3.根据权利要求1-2所述的氘代化合物及其药学上可接受的盐，其特征在于所述药学上可接受的盐选自甲磺酸盐、马来酸盐、盐酸盐或磷酸盐。
4.一种根据权利要求1-2所述的氘代化合物及其药学上可接受的盐在制备抗肿瘤药物中的应用。
5.根据权利要求1-2所述氘代化合物及其药学上可接受盐的药物组合物，其特征在于，所述药物组合物由所述氘代化合物及其药学上可接受的盐作为活性成分和药学上可接受的载体组成。
6.根据权利要求5所述的氘代HGFR抑制剂的药物组合物，其特征在于，所述药物组合物选自胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
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| CN116574169A (zh) * | 2023-07-10 | 2023-08-11 | 药康众拓(北京)医药科技有限公司 | 氘代gip/glp-1/gcg多受体激动剂药物及用途 |
| CN116854694A (zh) * | 2023-07-04 | 2023-10-10 | 北京浦润奥生物科技有限责任公司 | [1,2,4]三唑[4,3-b]哒嗪化合物的晶型及其制备方法和应用 |
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| CN116574169A (zh) * | 2023-07-10 | 2023-08-11 | 药康众拓(北京)医药科技有限公司 | 氘代gip/glp-1/gcg多受体激动剂药物及用途 |
| CN116574169B (zh) * | 2023-07-10 | 2023-12-26 | 药康众拓(北京)医药科技有限公司 | 氘代gip/glp-1/gcg多受体激动剂药物及用途 |
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